ABC Of AIDS

ABC

OF



AIDS

Fifth edition



Edited by Michael W Adler



ABC OF AIDS

Fifth Edition



ABC OF AIDS

Fifth Edition



Edited by MICHAEL W ADLER

Professor, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College, London



© BMJ Publishing Group 2001 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 1987 by the BMJ Publishing Group, BMA House, Tavistock Square, London WC1H 9JR www.bmjbooks.com First edition 1987 Second impression 1987 Third impression 1988 Fourth impression 1988 Fifth impression 1990 Second edition 1991 Third edition 1993 Fourth edition 1997 Sixth impression 1998 Seventh impression 2000 Fifth edition 2001 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0-7279-1503-7



Cover image: NIBSC/Science Photo Library. The image depicts AIDS virus. Coloured scanning electron micrograph of the surface of a T-lymphocyte (blue) infected with Human Immunodeficiency Virus (HIV). Cover design by Marritt Associates, Harrow, Middlesex Typeset by FiSH Books, London Printed and bound in Spain by Graphycems



Contents



Contributors Preface 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Development of the epidemic Michael W Adler The virus and the tests PP Mortimer, C Loveday Immunology of AIDS Peter Beverley, Matthew Helbert Natural history and management of early HIV infection Adrian Mindel, Melinda Tenant-Flowers Tumours in HIV Caroline H Bridgewater, Margaret F Spittle AIDS and the lung Rob Miller Gastrointestinal and hepatic manifestations Ian McGowan, Ian VD Weller Neurological manifestations Hadi Manji Treatment of infections and antiviral therapy Ian VD Weller, IG Williams HIV infection and AIDS in the developing world Alison D Grant, Kevin M De Cock Injection drug use-related HIV infection RP Brettle HIV infection in children Gareth Tudor-Williams, Diana Gibb HIV counselling and the psychosocial management of patients with HIV or AIDS Sarah Chippindale, Lesley French Palliative care and pain control in HIV and AIDS Rob George, Chris Farnham, Louise Schofield Control of infection policies IJ Hart, Celia Aitken Strategies for prevention John Imrie, Anne M Johnson Being HIV antibody positive Jonathan Grimshaw Having AIDS Caroline Guinness Index



vi viii 1 6 12 17 23 30 38 42 46 59 65 73 82 86 95 99 106 108 111



v



Contributors



Michael W Adler Professor, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College London, UK Celia Aitken Department of Virology, St Bartholomew’s and The Royal London, London, UK Peter Beverley The Edward Jenner Institute for Vaccine Research, Newbury, UK RP Brettle Consultant Physician, Regional Infectious Diseases Unit, Western General Hospital, Edinburgh; Reader in Medicine, University of Edinburgh, UK Caroline H Bridgewater Meyerstein Institute of Oncology, Middlesex Hospital, London, UK Sarah Chippindale Head of Health Adviser Services HIV/AIDS/GUM, Health Advisers Department, Mortimer Market Centre, London, UK Kevin M De Cock Director, CDC Kenya; Visiting Professor of Medicine and International Health, London School of Hygiene and Tropical Medicine, UK Chris Farnham Palliative Care Centre, Camden and Islington Community Trust and Royal Free and University College Medical School, University College London, UK Lesley French Clinical Psychologist, Camden and Islington CHSNHS Trust, London, UK Rob George Palliative Care Centre, Camden and Islington Community Trust and Royal Free and University College Medical School, University College London, UK Diana Gibb Senior Lecturer in Epidemiology/Consultant Paediatrician, Institute of Child Health, London, UK Alison D Grant Clinical Senior Lecturer, Clinical Research Unit, London School of Hygiene and Tropical Medicine, UK IJ Hart Department of Virology, St Bartholomew’s and The Royal London, UK Matthew Helbert Senior Lecturer, Department of Immunology, St Bartholomew’s Hospital, London, UK vi



Contributors

John Imrie Senior Research Fellow, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College London, UK Anne M Johnson Professor of Epidemiology, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College London, UK C Loveday Professor, Department of Retrovirology, Royal Free and University College Medical School, University College London, UK Hadi Manji Consultant Neurologist, National Hospital for Neurology and Neurosurgery and Ipswich Hospital, UK Ian McGowan Senior Director Clinical Science, Intrabiotics Pharmaceuticals, California, USA Rob Miller Reader in Clinical Infection, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College London, UK Adrian Mindel Director of the Sexually Transmitted Infection Research Centre and Professor of Sexual Health Medicine, Westmead Hospital, Sydney, Australia PP Mortimer Consultant Virologist, Central Public Health Laboratory, Virus Reference Division, London, UK Louise Schofield Clinical Nurse Specialist, Palliative Care Centre,Camden and Islington Community Trust and Royal Free and University College Medical School, University College London, UK Margaret F Spittle Consultant Clinical Oncologist, Meyerstein Institute of Oncology, Middlesex Hospital, London, UK Melinda Tenant-Flowers Consulted Physician, Department of Sexual Health, The Caldecot Centre, King’s Healthcare NHS Trust, London, UK Gareth Tudor-Williams Senior Lecturer in Paediatric Infectious Diseases, Imperial College School of Medicine at St Mary’s, London, UK Ian VD Weller Professor, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College, London, UK IG Williams Senior Lecturer, Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College, London, UK



vii



Preface



By December 2000 there were 17 538 adult and paediatric patients with AIDS in the UK and 43 774 screened and infected with HIV. Many of those with the virus are well, asymptomatic, and even unaware that they are infected, but others, although they have not yet developed AIDS, have physical, psychological, social, and occupational problems and require as much care as those with AIDS. We therefore need to be concerned not with “a few cases” but with a large number of people infected with the virus, who will be making demands on every part of the health and social services. New infections will occur, and the public health education campaign will need to continue. None of us should feel that the problem of HIV infection and AIDS is unimportant and that it will go away because of the campaign and the possible magic bullet of a cure or vaccine. We can all hope for these things but it would be a mistake to be lulled into a state of inertia and complacency. All of us will be concerned with AIDS for the rest of our professional lives. This book, originally written as weekly articles for the BMJ, attempts to give those doctors and other health care workers, who currently have had little experience of AIDS and HIV, some idea of the clinical, psychological, social and health education problems that they will become increasingly concerned with. Patients with HIV infection and AIDS spend most of their time out of hospital in the community. Admission is required only when an acute clinical illness supervenes. General practitioners and domiciliary and social services do not always feel skilled and knowledgeable enough to look after them. With the increase in the number of cases, the community services will have to be able and willing to cope. Again, I hope that this book will help to make people feel more skilled and comfortable about caring for patients with HIV and AIDS. This is the fifth edition of the ABC of AIDS; each chapter has been updated or rewritten. Michael W Adler



viii



1



Development of the epidemic



Michael W Adler



Box 1.1 Early history of the epidemic

1981 1983 1984 Cases of Pneumocystis carinii pneumonia and Kaposi’s sarcoma in the USA Discovery of the virus. First cases of AIDS in the UK Development of antibody test



The first recognised cases of the acquired immune deficiency syndrome (AIDS) occurred in the summer of 1981 in America. Reports began to appear of Pneumocystis carinii pneumonia and Kaposi’s sarcoma in young men, who it was subsequently realised were both homosexual and immunocompromised. Even though the condition became known early on as AIDS, its cause and modes of transmission were not immediately obvious. The virus now known to cause AIDS in a proportion of those infected was discovered in 1983 and given various names. The internationally accepted term is now the human immunodeficiency virus (HIV). Subsequently a new variant has been isolated in patients with West African connections – HIV-2.



Box 1.2 AIDS-defining conditions without laboratory evidence of HIV

• Diseases diagnosed definitively • Candidiasis: oesophagus, trachea, bronchi or lungs • Cryptococcosis: extrapulmonary • Cryptosporidiosis with diarrhoea persisting >1 month • Cytomegalovirus disease other than in liver, spleen, nodes • Herpes simplex virus (HSV) infection • mucocutaneous ulceration lasting >1 month • pulmonary, oesophageal involvement • Kaposi’s sarcoma in patient 1 month • Kaposi’s sarcoma at any age • Primary cerebral lymphoma at any age • Non-Hodgkin’s lymphoma: diffuse, undifferentiated B cell type, or unknown phenotype • Any disseminated mycobacterial disease other than M. tuberculosis • Mycobacterial tuberculosis at any site • Salmonella septicaemia: recurrent • HIV wasting syndrome • Recurrent pneumonia within 1 year • Invasive cervical cancer Diseases diagnosed presumptively • Candidiasis: oesophagus • Cytomegalovirus retinitis with visual loss • Kaposi’s sarcoma • Mycobacterial disease (acid-fast bacilli; species not identified by culture): disseminated • Pneumocystis carinii pneumonia • Cerebral toxoplasmosis



In 1993 the Centers for Disease Control (CDC) in the USA extended the definition of AIDS to include all persons who are severely immunosuppressed (a CD4 count 500 200–499 10% baseline Fever lasting at least 1 month Diarrhoea lasting at least 1 month



Box 4.5 Skin and mouth problems associated with HIV

Skin problems Miscellaneous Seborrhoeic dermatitis Fungal Tinea Cruris Pedis Other Candida Genital Perianal Other Pityriasis versicolor Bacterial Staphylococcal infection (impetigo) Acneform folliculitis Viral Herpes simplex (types 1 and 2) Oral Genital Perianal Other Varicella zoster Human papilloma virus Molluscum contagiosum Neoplastic Cervical dysplasia Mouth problems Hairy oral leukoplakia Dental abscesses/caries Gingivitis Candidiasis Ulceration Bacterial Herpetic Aphthous



Skin and mouth problems

Many skin problems occur in patients with HIV infection (Box 4.5). These may represent exacerbations of previous skin disease, or a new problem. Identical skin conditions occur in HIV-negative persons. However, in the immunocompromised, these common conditions may be more severe, persistent and difficult to treat. Many minor opportunistic infections (Group IVC2) manifest themselves on the skin and in the mouth. Seborrhoeic dermatitis is frequently seen and usually presents as a red scaly rash affecting the face, scalp and sometimes the whole body. This condition often responds well to 1% hydrocortisone and antifungal cream.



Figure 4.2 Hairy leukoplakia



Figure 4.3 Oral candida



Figure 4.4 Mouth ulcer



19



ABC of AIDS



Figure 4.5 Tinea cruris



Figure 4.6 Varicella zoster



Figure 4.8 Perianal herpes



Figure 4.7 Extensive seborrhoeic dermatitis



Other common dermatoses that respond to antifungal creams (for example Clotrimazole) include tinea cruris and pedis and candidiasis. Folliculitis often responds to 1% hydrocortisone and antifungal cream, impetigo to antibiotics and shingles to aciclovir, valaciclovir or famciclovir. Recurrent perianal or genital herpes may become more troublesome, with recurrences lasting longer and occurring more frequently; if this persists for more than 3 months it is considered an AIDSdefining opportunistic infection (Group IVC1). Treatment with long-term acyclovir, valaciclovir or famciclovir suppression is often required. Genital and perianal warts are common, difficult to treat and frequently recurrent, and high-grade cervical dysplasia is seen more often in HIV-infected women. Mouth problems are also common, cause considerable distress and when severe may result in difficulty with eating and drinking. Oral candida can be managed with topical or systemic antifungals (eg, nystatin, ketoconazole or fluconazole). If dysphagia develops, oesophageal candidiasis should be suspected 20



and investigated. Oral hairy leukoplakia can be differentiated from oral candida by its characteristic distribution along the lateral borders of the tongue and the fact that it cannot be scraped off. Although unsightly, this condition which is due to Epstein–Barr virus reactivation is painless and temporary remission can be obtained with acyclovir, valaciclovir or famciclovir. Other oral conditions including dental abscesses, caries, gingivitis and oral ulceration (herpetic or bacterial) may occur. Mouth ulcers may be particularly difficult to treat and expert specialist assessment is recommended. Metronidazole, acyclovir, 0.2% chlorhexidine mouthwashes and analgesic sprays may all be effective depending on the cause and, in extreme cases, thalidomide has been used. Maintenance of good oral hygiene and dental care are important.



HIV and haematological problems

Lymphopenia with depression of the CD4 cell subset is a marker for HIV disease. Mild to moderate neutropenia and a



Natural history and management of early HIV infection

normochromic, normocytic anaemia of unknown origin are often seen but usually have no adverse effect on HIV-infected individuals. Severe anaemia or neutropenia should be investigated for other underlying causes. Thrombocytopenia is common in HIV disease and, only if persistent, causing bleeding and less than 20 10 9/litre warrants treatment with antiretrovirals which is usually effective. Many therapies used to treat HIV may be toxic to bone marrow.



Risk of progression and the value of surrogate markers

One of the hardest problems confronting the physician dealing with an asymptomatic patient with HIV infection is predicting how soon that patient will progress to symptomatic disease or AIDS. This issue is important, firstly in terms of counselling and secondly, to decide which patients may benefit from antiretroviral treatment or prophylaxis to prevent opportunistic infections. Variables associated with rapid disease progression include a symptomatic PHI, older age at diagnosis and receiving a large inoculum of virus, for example via a contaminated transfusion from a donor with a high viral load. The effect of prophylaxis against opportunistic infections (for example cotrimoxazole for pneumocystis and toxoplasmosis) has been to delay the onset of AIDS and to change the pattern of disease represented by the first AIDS-defining illness. Antiretroviral treatment has independently been shown to increase survival before and after AIDS. Some infected individuals do not progress for many years and work is in progress to determine whether this is due to their genetic makeup, amount of viral inoculum, characteristics of the infective virus or their immune system. Many laboratory indices have been used as prognostic indicators, both to evaluate disease progression and treatment efficacy. The most widely used are the CD4 absolute lymphocyte count or percentage and the viral load. At least two CD4 measurements should be obtained before initiating prophylaxis for opportunistic infections or antiretroviral therapy, as the CD4 count is subject to diurnal and seasonal variation and reduced by intercurrent infection. A fall in CD4 cells is associated with disease progression, particularly if the rate of decline is rapid. Likewise, at least two viral loads, from the same laboratory using the same assay, should be obtained to avoid interassay variation. Some HIV clades are more difficult to monitor with certain assays and the laboratory should be informed of the country of origin of the patient. Patients who may need close monitoring include individuals whose CD4 count falls below 350 cells/mm 3, those with a rapidly declining CD4 count, those with a rising viral load and patients who are symptomatic as they may all be candidates for antiretroviral therapy. Patients who present with persistent constitutional symptoms, mouth or skin problems should be considered for antiretroviral therapy irrespective of CD4 count and viral load. These issues are discussed further in the chapters on treatment of infections and antiretroviral agents.



Figure 4.9 Vesicles of varicella zoster



Figure 4.10 Cervical intraepithelial neoplasia



General management of HIV-infected people

One of the most important aspects of dealing with any HIVinfected person is confidentiality (Box 4.6). Maintaining confidentiality might be complicated: for example the patient’s family or friends may not know his or her diagnosis or sexual orientation; people at work (or school) may seek medical information (especially if the individual is having time off



Box 4.6 General management of the HIV-infected person

• • • • • Protect confidentiality Medical issues Psychological support (patient, family and friends) Avoidance of transmission Other issues (dental treatment, insurance, work, or school, etc.)



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ABC of AIDS

work); or the person may fear that information may inadvertently be given to third parties. Special precautions may be required, firstly to reassure the patient that confidentiality is protected and, secondly, to limit any unwarranted dissemination of confidential information. Issues related to partner notification are discussed in chapter 13. The routine medical management of these individuals is usually straightforward. They should be seen regularly, for example every three to six months. At each visit the patient’s weight should be recorded and special attention given to mouth or skin problems and, if necessary, they should be referred to the appropriate specialist. Screening for STDs and hepatitis viruses should be offered if the individual is at risk and hepatitis A and B vaccines can be safely given. Repeating a full blood count and measuring the CD4 count and viral load every three to six months allows early detection of actual or imminent immune dysfunction. Patients should be advised to reattend if they develop any symptom, especially those suggestive of opportunistic infections or cancers, for example shortness of breath, cough, haemoptysis, pain or difficulty in swallowing, diarrhoea, weight loss, fevers, headaches, fitting, altered consciousness or purple spots on their skin. Other symptoms may indicate increased viral replication and the need to consider treatment. Psychological and emotional support of the infected individual, the family and friends are a vital aspect of management (see chapter 13). HIV antibody positive persons should also be advised about reducing the risk of transmitting HIV to others and reducing their own risk of receiving different, possibly drug resistant, strains of HIV. Advice concerning safer sex, safer needle use, pregnancy, breastfeeding and children should also be provided (see chapter 16). Patients should be advised to tell their dentists about their infection, and it may sometimes be necessary to refer them to a dental unit with an interest in HIV-related problems. The physician may also be asked to advise about insurance, work, immigration, travel passes, housing and disability benefit. Patients should be referred to the relevant legal or benefit agency as soon as possible. Infected individuals will often have considerable difficulty in obtaining life insurance as most insurance companies ask specific questions about the infection and either refuse insurance or charge very high premiums. Finally, patients should be told that being positive is no barrier to employment provided there is no chance of their body fluids entering another person or of them transmitting an opportunistic infection, such as tuberculosis, by coughing. It is worth noting that for notifiable diseases such as TB, standard, confidential public health notification procedures still apply. Because of widespread misconceptions about infectivity which are still prevalent, information about the individual’s HIV status should never be divulged to employers without their written consent.



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5



Tumours in HIV



Caroline H Bridgewater, Margaret F Spittle



The United States Center for Disease Control recognises three malignancies as AIDS-defining conditions. These are Kaposi’s sarcoma, intermediate or high grade B-cell non-Hodgkin’s lymphoma (NHL) and cervical carcinoma. Primary central nervous system lymphoma is a rare B-cell NHL that is often considered separately from the other NHLs. Other malignancies are known to have an increased incidence in HIV whilst not being AIDS-defining, for example Hodgkin’s disease. All malignancies are more aggressive in HIV positive patients than in the general population and usually present at advanced stages. The investigation and treatment of suspected malignancy is complicated by unusual presentations and sites of disease, concomitant infections and immunosuppression. Malignancies may occur at different points in the disease process for different individuals and management must be tailored to the patient’s overall maximum benefit. There are many new developments in the understanding of the pathogenesis of AIDS-related malignancies and in the future these will inform new therapies. In the last few years alone highly active antiretroviral therapy (HAART) has had a great impact on the incidence and natural history of some of these malignancies. As opportunistic infections are more easily treated and patients live longer the malignancies are likely to become relatively more common. The incidence of AIDS-related malignancies varies within the different population groups with HIV and as affected groups evolve there will doubtless be a change in the incidence of malignancies seen in the UK. With these rapid changes optimal treatment strategies are controversial and patients should be entered into clinical trials.



Table 5.1 Risk of malignancies in HIV-positive patients

Relative risk compared to HIV-negative population 716–972 71–141 ~100 ? 5–9 3.5–5 3



Malignancy Kaposi’s sarcoma NHL Primary CNS lymphoma (PCNSL) Cervical cancer Hodgkin’s disease Anal cancer Testicular germ cell tumours



Viral co-factor KSHV (HHV8) EBV EBV HPV EBV HPV ?



Box 5.1 Clinical groups of patients with Kaposi’s sarcoma (KS)

• • • • “Classic” KS: elderly, predominantly male, Jewish or Eastern European “Endemic” or African KS (various types) Immunosuppression-related KS (patients with transplants) “Epidemic” or AIDS-related KS



Kaposi’s sarcoma

Among the first reported illnesses amongst homosexual men in the USA in 1981 was Kaposi’s sarcoma (KS), with 20–40% of HIV-infected homosexual men suffering KS. Hitherto KS had been known in three forms. In elderly Jewish or Eastern European patients as “classic” KS, in sub-Saharan Africa as “endemic” KS, and more recently in transplant and other immunosuppressed patients. KS currently remains the most frequent neoplastic condition in AIDS. Aetiology The uneven geographical distribution of KS had long suggested that environmental factors were aetiologically important. Epidemiological observations that KS initially occurred in clusters in the HIV population and that it was 20 times more likely in homosexual men than other risk groups suggested a sexually transmitted cofactor. Work in the biological and statistical fields has gone on to establish causality. Whilst no biological pathway has yet been identified, there is now sufficient evidence to state that a DNA virus, Kaposi’s sarcoma-associated herpes virus (KSHV) also known as human herpes virus 8 (HHV8), is an essential, although not necessarily a sufficient, cause of KS. This evidence has primarily come from longitudinal studies showing that KSHV infection precedes KS. This is consistent with analogous evidence of other herpes viruses, for example Epstein–Barr virus (EBV) being oncogenic. KSHV has been



Figure 5.1 Classical Kaposi’s sarcoma



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ABC of AIDS

detected in tissue biopsies taken from patients with African and classical KS as well as AIDS-related cases. KSHV can be sexually transmitted and seroconversion has been noted following renal transplantation. In endemic areas non-sexual horizontal and vertical spread are the proposed dominant modes of transmission. The evidence for this is the age-dependent increase in KSHV seroprevalence in prepubescent children in studies from Gambia and Uganda and the greater (29% compared to 0%) seropositivity rate in children born to KSHV seropositive women in South Africa. Histopathology The tumours have a characteristic appearance, consisting of groups of spindle cells separated by slits giving a sieve pattern. These spindle cells derive from primitive mesenchymal cells. Red cells are often seen in the slits and early lesions may consist almost entirely of bizarre endothelium-lined vascular spaces in the dermis with few spindle cells. The tumour stains positive for factor VIII and smooth muscle-specific -actin on immunocytochemistry staining. The following cytokines have been shown to promote the growth of KS cells in vitro: interleukin 6 (IL-6), tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Oncostatin M and granulocyte colonystimulating factor (GCSF). It may be possible to exploit this therapeutically by inhibiting these cytokines. Kaposi’s sarcoma is a multifocal process rather than a metastatic one. Clinical presentation The classic form tends to follow a very indolent course producing large ulcerated plaques on the lower legs. It shows a strong male preponderance and as most affected individuals are elderly their KS causes significant morbidity but not mortality. Endemic KS follows a more aggressive course in younger adults with more florid skin lesions and lymph node involvement. Death occurs due to widespread systemic involvement. In young children the lymphadenopathic variant is most commonly seen. In the non-HIV immunosuppressed patient the lesions of KS may improve with reduction or cessation of the immunosuppression. In the UK these forms are all rare and most cases of KS are AIDS related. The presentation of KS in AIDS is variable but the disease tends to become increasingly aggressive and may be lethal. Mucocutaneous lesions begin as flat dusky red papules progressing over weeks or months to vary from a few scattered nodular lesions to large plaques. The legs, trunk, arms, face, hard palate and penis are common sites with associated “woody” oedema and ulceration predominantly affecting the lower limbs. KS on the feet make walking difficult and painful. Other mucocutaneous lesions often cause distress because of their disfiguring appearance. All organs other than the central nervous system may be affected and the presence of visceral disease is predicted by mucocutaneous disease; one third of respiratory “episodes” in patients with cutaneous KS are due to pulmonary KS. The most common visceral lesions are pulmonary and gastrointestinal. Lymph node disease is also common and may cause venous compression resulting in gross peripheral oedema. Presentation of pulmonary KS is usually with exertional dyspnoea but may be with cough or haemoptysis. Chest radiograph changes are often non-specific with interstitial infiltrates, pleural effusions and mediastinal lymphadenopathy. Further information is 24



Figure 5.2 Classical nodular Kaposi’s sarcoma



Figure 5.3 Lymphangioma-like Kaposi’s sarcoma



Figure 5.4 Kaposi’s sarcoma



Tumours in HIV

gained by bronchoscopy and CT; if possible bronchial biopsy should be avoided as bleeding may be heavy (see chapter 6). Lesions may occur along the length of the gastrointestinal tract from the palate to the anus and diagnosis is by endoscopy. KS in the oral cavity and oesophagus may cause pain but is usually asymptomatic. Bleeding may occur from lesions throughout the gastrointestinal tract and patients may also suffer protein-losing enteropathy and diarrhoea. KSHV is also found in two rarer malignancies, primary effusional lymphoma (a subset of B-cell non-Hodgkin’s lymphoma) and multicentric Castleman’s disease, a lymphoid malignancy which also has an increased incidence in AIDS. Incidence KS was the AIDS-defining diagnosis in 30% of patients in the 1980s but this has now fallen. The reduction may be attributed to changes in sexual practices as well as the advent of antiretroviral therapy. KS commonly precedes opportunistic infections and with improvements in treating such infections KS is increasingly common as the cause of death for AIDS patients. Hence whilst the incidence of KS is falling the prevalence is increasing. The deaths of almost 30% of AIDS sufferers are now accounted for by visceral and particularly pulmonary KS. Treatment Treatment must be tailored to the site and extent of KS and to the patient’s underlying clinical condition. The aim of treatment is resolution of symptoms and prolongation of life. Cure is currently impossible due to the disseminated nature of the condition and its poorly understood pathogenesis as well as the underlying AIDS. HAART has reduced the need for second-line therapies by increasing median time to treatment failure as well as reducing the incidence of KS. There are reports of KS regression with HAART and no other treatment. Local treatment is important for cosmesis of cutaneous lesions. Superficial radiotherapy is given using 100 kV X-rays applied directly to the skin or palate. A dose of 8 Gy in a single fraction achieves good palliation in 70% of lesions, particularly in early KS with little haemosiderin staining. The area of the lesion is treated with a margin using a lead cutout to protect surrounding tissues. The dose should be given in divided doses on consecutive days (fractionation) to sensitive areas such as the soles or face. Radiotherapy can be repeated if further regression is required or relapse occurs. Alternative treatments include camouflaging with cosmetics and intralesional injection with vinblastine or interferon. Palatal, bronchial and oesophageal KS can also be treated with radiotherapy. It is particularly useful to stop bleeding. For extensive mucocutaneous disease or visceral involvement chemotherapy is the preferred option. Several regimens are available and choice of regimen depends on coexistent pathologies and, in some countries, availability and price. Sadly many of the newer treatments with better side-effect profiles are prohibitively expensive for the developing nations where KS is prevalent. In patients with relatively well preserved immune function interferon- is a useful treatment. Bleomycin and vincristine in combination was initially the commonest regimen giving a response rate of 50–60% with acceptable side-effects. This has now largely been superseded by the liposomal preparations of doxorubicin and daunorubicin (anthracycline antibiotics) following trials which showed comparable efficacy and reduced toxicity. A liposome is a sphere made of phospholipid bilayers which can be selectively distributed to tumours allowing local drug deposition when the liposome breaks down. Liposomal packaging allows higher doses of these drugs to be delivered with fewer side-effects.



Figure 5.5 Kaposi’s sarcoma on the chest



Figure 5.6 Cutaneous Kaposi’s sarcoma



Figure 5.7 Palatal Kaposi’s sarcoma



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ABC of AIDS

Cumulative doses of non-liposomal anthracyclines are limited at 450–550 mg/m 2 by cardiotoxicity and in a chronic condition like KS long or repeated courses of chemotherapy may be required. More recently there has been increased interest in the use of antiangiogenics and trials are currently underway on the tyrosine kinase receptor inhibitor SU5416 and thalidomide. This has been fired by studies showing the presence of vascular endothelial growth factor and basic fibroblast growth factor in KS tissues. Paclitaxel, a newer cytotoxic, is also undergoing trials. Common side-effects are those shared with many other cytotoxics including nausea, vomiting, myelosuppression and mucositis. In the AIDS patient, with concomitant diseases and multidrug therapy including HAART, it can be difficult to find the root cause of such symptoms. Box 5.2 Summary of malignancies

AIDS-defining malignancies • Kaposi’s sarcoma • High/intermediate grade non-Hodgkin’s lymphoma including primary CNS lymphoma • Cervical carcinoma Other malignancies with increased incidence • Hodgkin’s disease • Ano-genital squamous cell carcinoma • Testicular germ cell tumours



Non-Hodgkin’s Lymphoma

The occurrence of non-Hodgkin’s lymphoma (NHL) was known to complicate immunodeficiency states before the advent of HIV. Up to 20% of HIV positive people may ultimately develop NHLs and it is the presenting diagnosis in 3% of patients. In immunodeficiency NHLs are commonly extranodal. Aetiology Both HIV itself and its related opportunistic infections may cause polyclonal B-cell expansion which is probably cytokine and antigen driven. Patients with AIDS have impaired immunity to EBV when compared to HIV negative EBV-infected individuals and EBV is itself likely to cause polyclonal B-cell proliferation. AIDS lymphomas have modified immunoglobulin variable regions which are consistent with antigen drive as an important factor in lymphomagenesis. Macrophages, acting as antigen-presenting cells, also appear to be clonally expanded. When CD4+ T-cell levels fall, antigen levels rise and the risk of lymphomagenesis increases. Such proliferation allows for sequential genetic errors leading to a monoclonal and hence malignant transformation. Pathology Systemic lymphomas in AIDS are pathologically diverse. A diffuse small non-cleaved subset is unique to HIV patients and is associated with elevated IL-6 and soluble CD23 levels. It is less frequently associated with EBV than the diffuse immunoblastic or diffuse large cleaved cell subtypes. Histological type does not currently affect prognosis although the different subtypes are clinically separate. All these subtypes are high grade. Immunohistochemistry reveals positive staining for CD20 in 90% of B-cell lymphomas. Clinical presentation NHL can occur at any stage of immunodeficiency with approximately one-third of patients with AIDS-related NHL having a previous AIDS diagnosis. Stage III or IV disease accounts for 70%–80% of cases (see Box 5.3) with a majority of patients presenting with extranodal disease. Common sites are the gastrointestinal tract, liver and bone marrow. Bone marrow involvement occurs in 20%–30% of cases and exacerbates chemotherapy-induced bone marrow toxicity. NHL is associated with B symptoms of sustained fever greater than 38ºC, weight loss (greater than 10% of body weight) and night sweats. All of these symptoms may occur in an HIV positive patient without NHL and so are of limited diagnostic and prognostic use in this clinical setting.



Figure 5.8 HIV-related non-Hodgkin’s lymphoma



Box 5.3 Ann Arbor: classification of lymphoma

Stage I Stage II Single lymph node region +/– local spread to extralymphatic tissue (E) Two or more node regions on same side of diaphragm +/– local spread to extralymphatic tissue (E) Involved nodes both sides of the diaphragm Diffuse or disseminated involvement of one or more extralymphatic organs



Stage III Stage IV



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Tumours in HIV

Prognosis is poor with a median survival of 4–6 months in spite of an often good early response to treatment. A previous AIDS-defining illness, a CD4 count 250 10 6/l and complete response to treatment. Ano-genital squamous cell carcinoma Anal cancer like cervical cancer is related to human papillomavirus. HIV positive patients are two to six times more likely than HIV negative persons to have anal human papillomavirus infection. Persistence of infection is inversely related to CD4 count. Low-grade anal intraepithelial neoplasia is more likely to progress to high grade anal intraepithelial neoplasia in HIV positive patients. However it remains unclear whether HIV directly affects the development of anal carcinoma. There is a threefold increase in incidence in testicular germ cell tumours in homosexual HIV positive men. Seminoma is much more common than teratoma. Lung cancer of all histological types, non-melanomatous skin cancers, angiosarcomas and paediatric leiomyosarcomas may all be increased in HIV infection. Lung cancers occur at an earlier age and have a poorer prognosis in the HIV positive population. This varied response highlights the continued need for innovative treatments, both in terms of chemotherapy and the manipulation of the immune response.



Current research and the future

The rapidly increasing evidence on viral involvement in AIDSassociated malignancies suggests novel molecular targets for drug discovery using drug screening and molecular modelling. Vaccines for cancers occurring in patients with human papilloma viruses associated with cervical and ano-genital carcinoma and EBV in haematological malignancies are currently being researched. Other therapeutic approaches include biological therapy (for example IL-2, IL-12, IFN- ), immune-based therapy (for example antigen-presenting cells and monoclonal antibodies against B-cell targets) and angiogenesis inhibitors. New assays to detect KSHV are now in use. Further work is needed on the cofactors influencing the progression of KSHV seropositive individuals to the development of KS. The antiherpes drug cidofovir has activity against KSHV but it remains to be seen as to whether it is an effective treatment for KS. To improve existing treatments the effects on the underlying HIV infection and the impact on the immune system of antitumour therapy need to be identified. As anti-HIV therapies have a clinical effect on tumour incidence, complex issues of drug–drug interactions and overlapping toxicities must be considered. In the HAART era NHL is likely to become the most common malignancy associated with AIDS — new treatment strategies are urgently needed as treatment is currently extremely disappointing. Possibilities include the exploitation of cytokine networks, as we already know that these patients have low levels of IL-2 and IFN- but elevated IL-6. Treatment with low-dose IL-2 is already undergoing trials.



The effect of HAART

With the improved control of HIV replication brought about by combination antiretroviral therapy, the frequency of AIDSrelated malignancy is falling. The incidence of KS has dropped by approximately 75%. Sadly there has been a smaller decline in the incidence of NHL, although primary CNS lymphoma has also markedly declined. The lack of change in the incidence of systemic lymphoma reflects a heterogeneous and complex pathophysiology, not as susceptible to the influence of HAART as KS. The effect on HPV-associated anogenital squamous cell carcinoma has also been disappointing.



29



6



AIDS and the lung



Rob Miller



The lungs are commonly affected in patients infected with HIV, with over 60% of patients having at least one respiratory episode during the course of their disease. When immune responses are relatively well preserved in early HIV infection the pattern of respiratory infections is similar to that found in the general population, although they occur with greater frequency. The risk of opportunistic infections and tumours increases as progressive HIV-induced immunosuppression occurs. Over recent years there have been several changes in the pattern of lung disease seen in those infected with HIV. These changes may be accounted for by the widespread availability and uptake of prophylaxis for Pneumocystis carinii pneumonia and combination antiretroviral therapy (also known as highly active antiretroviral therapy or HAART).



Box 6.1 HIV-associated respiratory disease

Infections Bacterial bronchitis/sinusitis Bacterial pneumonia Tuberculosis P. carinii pneumonia Fungal pneumonia Cytomegalovirus pneumonitis Malignancy Kaposi’s sarcoma Lymphoma Lung cancer Non-malignant conditions Lymphoid interstitial pneumonitis Non-specific pneumonitis



Investigations

Symptoms of cough and dyspnoea with or without fever and sweats identify the presence of respiratory disease in HIV positive patients, but these are non-specific and symptomatic patients should be investigated.



Non-invasive investigations These tests should ideally allow a specific diagnosis to be made and a therapeutic response monitored by a quick, cheap and universally available method. Unfortunately, none of these tests fulfils the criteria but they do help to: • Determine the presence or absence of pulmonary disease. • Assess disease severity. • Determine if an invasive test is indicted to make an aetiological diagnosis.



Box 6.2 Investigation of respiratory disease

Non-invasive tests Chest radiograph Arterial blood gases or oximetry Pulmonary function tests Invasive tests Induced sputum Fibreoptic bronchoscopy and bronchoalveolar lavage with or without transbronchial biopsy Open lung biopsy



Chest radiology The chest radiograph may be normal in HIV positive patients with respiratory disease caused by P. carinii pneumonia. The most common abnormality seen in patients with pneumocystis pneumonia is bilateral perihilar haze which may be very subtle and easy to miss. More severely unwell patients may have more diffuse interstitial shadowing which may progress to severe consolidation with “white out” throughout both lung fields, with sparing of the apices and costophrenic angles. These radiographic appearances are non-specific and may also be seen in pyogenic bacterial, mycobacterial and fungal infection, and also in Kaposi’s sarcoma and lymphoid interstitial pneumonitis. Between 5% and 10% of patients with pneumocystis pneumonia have atypical chest radiographs showing cystic changes, upper lobe infiltrates mimicking tuberculosis, hilar or mediastinal lymphadenopathy or focal consolidation. The chest radiograph in pneumocystis pneumonia may deteriorate very rapidly from being normal to showing severe abnormality in just a few days. By contrast, radiographic recovery can be slow. Nodular shadowing, adenopathy and pleural effusions on the chest radiograph suggest Mycobacterium tuberculosis, Kaposi’s sarcoma or lymphoma.



Figure 6.1 Chest radiograph of patient with early pneumocystis pneumonia



30



AIDS and the lung

Arterial blood gases and oximetry Hypoxaemia and a widened alveola–arterial oxygen gradient are very sensitive for the diagnosis of pneumocystis pneumonia but may also occur in other conditions. Exercise-induced arterial desaturation detected by oximetry is also sensitive for the diagnosis of pneumocystis pneumonia; desaturation may persist for several months following recovery from P. carinii pneumonia and occur also rarely in cytomegalovirus pneumonitis but is unusual in other respiratory conditions. Pulmonary function tests The single breath carbon monoxide transfer factor (TLCO), transfer coefficient (KCO), total lung capacity (TLC) and vital capacity (VC) may all be reduced in patients with pneumocystis pneumonia. Reductions in TLCO to 70% of predicted normal occur in HIV positive patients with pneumocystis and other respiratory disease, including Kaposi’s sarcoma and bacterial infections, so this finding is not specific. Invasive tests These allow an aetiological diagnosis to be made. Sputum induced by hypertonic saline This procedure must be carried out away from other patients and staff in a separate room, ideally with “negative pressure” facilities in order to reduce the risk of nosocomial transmission of infection including tuberculosis. The patient inhales 20–30 ml of 2.7% (3 N) saline through an ultrasonic nebuliser. Saline deposits in the peripheral airways and alveoli, causing irritation and inducing bronchial secretion. Fluid is also drawn into the airways from the interstitium, loosening inflammatory exudate and casts from alveoli. These are mobilised by the mucociliary escalator and move centrally where they are coughed out by the patient. Careful preparation of the patient is needed, including starving for several hours before the procedure and rigorous cleansing of the mouth to remove oral debris so that the sputum sample is not contaminated (food debris and squames take up stain and make analysis difficult). Purulent samples of sputum suggest a bacterial cause. P. carinii infection is usually found in clear “saliva-like” samples that become viscid on cooling to room temperature. Fungal infection and mycobacterial infection may also be diagnosed by this technique. Many centres do not carry out sputum induction because of the need for special equipment and the low yield when the technique is compared with fibreoptic bronchoscopy, both for the diagnosis of pneumocystis pneumonia and other pathogens. Some patients find sputum induction unpleasant and become nauseated or dyspnoeic. Arterial desaturation may also occur during the procedure. Fibreoptic bronchoscopy Bronchoscopy allows inspection of the bronchi to be carried out and lesions of Kaposi’s sarcoma may be identified. Bronchoalveolar lavage is routinely carried out from the middle lobe or from the area of maximum abnormality seen on the chest radiograph. Transbronchial biopsies are now rarely done as they add little to the diagnostic yield for P. carinii and other diagnoses, and the technique is associated with adverse effects including haemorrhage and pneumothorax. If transbronchial biopsy is not performed a diagnosis of non-specific or lymphocytic interstitial pneumonitis might be missed. Open lung biopsy It is rarely necessary to carry out open lung biopsy because of the high yield from bronchoalveolar lavage. This investigation may be necessary if fibreoptic bronchoscopy and lavage fail to



Figure 6.2 Chest radiograph of patient with severe pneumocystis pneumonia



Figure 6.3 Cytology preparation of induced sputum showing many cysts of Pneumocystis carinii (Grocott’s methenamine silver stain)



Box 6.3 Open lung biopsy

If fibreoptic bronchoscopy and lavage fail to identify diagnosis or where patient with bronchoscopic diagnosis deteriorates despite specific treatment



31



ABC of AIDS

identify a diagnosis or in cases where a patient with a bronchoscopic diagnosis, deteriorates despite specific treatment. The presenting clinical features and treatment of the common pulmonary manifestations of HIV disease are described below. Table 6.1 Grading of severity of P. carinii pneumonia

Mild Symptoms and rest signs Increasing exertional dyspnoea, with or without cough and sweats Moderate Dyspnoea on Severe Dyspnoea at



Pneumocystis carinii pneumonia

Despite widespread use of anti-pneumocystis prophy!axis and HAART, P. carinii pneumonia remains a common AIDS-defining diagnosis in patients who at presentation with pneumonia are unaware of their HIV serostatus or who, despite knowing they have HIV infection, are non-compliant with or intolerant of their prophylaxis and/or HAART. Patients complain of a non-productive cough and increasing dyspnoea (over two to three weeks or more); they may also have fever and sweats. The chest radiograph may be normal or show interstitial infiltrates: in severe pneumonia there may be widespread alveolar consolidation. Treatment It is important to assess the severity of the pneumonia in order to choose appropriate treatment, as some drugs are ineffective in severe disease. High-dose co-trimoxazole remains the “gold standard” treatment. Treatment is for 21 days, given intravenously for the first 10–14 days, diluted in 1 in 25 of 0.9% saline, subsequently, orally. Patients with mild disease may be treated with oral co-trimoxazole from the outset. The principal side-effects are nausea and vomiting, leucopenia and rash. Routine use of folic or folinic acid does not prevent leucopenia and may be associated with increased therapeutic failure. HAART is usually stopped while co-trimoxazole is being given to avoid profound myelosuppression. Conventionally used doses of co-trimoxazole (20 mg/kg day of the trimethoprim component) may be excessive: dose reduction to 75% of this dose (to maintain serum trimethoprim concentrations at 5–8 µg/ml) has equivalent efficacy and reduced toxicity. Alternative treatment regimens include: Clindamycin–primaquine combination (clindamycin 600 mg 4/day iv or orally and primaquine 15 mg/day orally) has been used in patients intolerant of, or failing to respond to, co-trimoxazole. Principal side-effects are rash, nausea and vomiting, and leuco(neutro)penia. Dapsone–trimethoprim (100 mg/day dapsone and 20 mg/kg/day trimethoprim) given orally for 21 days is as effective as oral co-trimoxazole in mild to moderate disease and is better tolerated by patients. Side-effects include methaemoglobinaemia and hyperkalaemia, nausea and rash. Atovaquone suspension (750 mg 2/day) given orally for 21 days is less effective (and less toxic) than either co-trimoxazole or pentamidine for mild to moderate disease. Absorption from the gut is variable but may be increased if taken with food. Pentamidine is not often used because of significant toxicity and because other regimens have similar efficacy and less toxicity. It is given at a dose of 4 mg/kg/day (of the isethionate salt) given diluted in 250 mg 5% dextrose by slow intravenous infusion (over 2 hours); it should not be given by intramuscular injection. The major side-effects are hypotension and hypoglycaemia; nephrotoxicity with increases in creatinine and urea concentrations may occur. Dose reduction to 3 mg/kg/day is associated with reduced toxicity but may be less effective. Blood pressure and blood glucose concentrations should be closely monitored. Response to pentamidine (defervescence of fever, reduction in dyspnoea and improvement in blood gases) may take longer (4–7 days) than intravenous co-trimoxazole. 32



minimal tachypnoea at exertion, rest, persistent occasional fever, cough dyspnoea at rest, fever with or without sweats Blood gas PaO 2 PaO 2 PaO 2 tensions (room air) >11.0 kPa 8.0–11·0 kPa 96% 91–96% 75% but this procedure is very invasive and should probably be avoided as patients with pulmonary Kaposi’s sarcoma have a poor prognosis. Treatment Chemotherapy most often consists of bleomycin 10 000 units/m 2 and vincristine 2 mg once every three weeks. Liposomal formulations of daunorubicin and doxorubicin may 34



Figure 6.7 Chest radiograph of pulmonary Kaposi’s sarcoma showing multiple pulonary nodules



Figure 6.8 Chest radiograph of pulmonary Kaposi’s sarcoma showing bilateral pleural effusions and interstitial infiltrates



AIDS and the lung

also be used as single-agent chemotherapy. Treatment of pleural effusions (which occur secondary to Kaposi’s sarcoma on the visceral pleura or to mediastinal glands) is problematical. Chemical pleuradesis is rarely successful and radiotherapy has not been shown to be of value.



Tuberculosis

Unlike opportunistic infections in AIDS tuberculosis is also infectious for healthy individuals. Tuberculosis is a potent stimulator of cell-mediated immunity and so may speed up the natural history of HIV disease. The incidence of tuberculosis is currently increasing in the USA; this is directly attributable to the effects of HIV in certain populations. No increase has occurred yet in Britain but the unpredictable features of the HIV epidemic in heterosexuals, migrants and injecting drug users means careful vigilance is required. Tuberculosis can precede the development of AIDS, be diagnosed at the same time or occur at any time during established AIDS. Tuberculosis in HIV positive patients is AIDS defining and in the USA, the UK and most other European countries is a statutorily notifiable disease. Over two thirds of cases of tuberculosis in HIV-infected patients present with pulmonary disease. Clinical presentation varies according to the stage of HIV disease. Early on, with relatively well preserved cell-mediated immunity, pulmonary tuberculosis resembles classic adult post-primary disease with upper lobe infiltrates and cavitation; the tuberculin test is usually positive and acid and alcohol fast bacteria (AAFB) are frequently seen when sputum is examined by microscopy. With advanced HIV disease and destroyed cell immunity, presentation is non-specific with fever, weight loss and fatigue, with or without cough. Patients with low CD4 counts 200 10 6/l may recover spontaneously. Treatment is supportive as no agent has shown convincing efficacy. The organism is heat sensitive and immunosuppressed patients are advised to boil water for drinking purposes. Microsporidia are also an important cause of diarrhoea as well as being associated with hepatitis, peritonitis, sclerosing cholangitis, sinusitis, and renal failure. Diagnosis is difficult as the spores are only 1–5µm in diameter. A number of centres have reported successful identification of spores in stool using trichrome and fluorescent stains but morphology is best determined using electron microscopy. Albendazole has shown promise in AIDS patients with microsporidiosis but may only be active against Encephalitozoon intestinalis and not Enterocytozoon bienusi. Isospora belli is an infrequent cause of diarrhoea in AIDS patients in the USA and Europe but accounts for up to 25% cases of chronic diarrhoea in patients in tropical and subtropical countries. Response to trimethoprim– sulphamethoxazole has been described. Cyclospora sp. is the most recent protozoan to be associated with diarrhoea in AIDS. It appears to be more common in the developing world and in returning travellers and like Isospora belli appears to be sensitive to trimethoprim–sulphamethoxazole. Other protozoa including Entamoeba histolytica are frequently identified in stools from HIV-infected homosexual men but appear not to be pathogenic. Cytomegalovirus colitis occurs in less than 5% of patients with AIDS. Symptoms include bloody diarrhoea, abdominal pain, and fever. Sigmoidoscopy may show diffuse erythema and mucosal ulceration. Diagnosis is histopathological and is made on the basis of characteristic intranuclear “owl’s-eye” inclusion bodies or detection of CMV antigen with monoclonal antibodies. Treatment is with ganciclovir or foscarnet. Adenoviruses have been identified by culture and electron microscopy in HIV-infected homosexual men with diarrhoea. No specific treatment is available. Box 7.2 Infective causes of diarrhoea

• Bacteria • campylobacter, salmonella, shigella • atypical mycobacteria • Clostridium difficile Protozoa • cryptosporidium • microsporidia • Isospora belli and cyclospora Viruses • cytomegalovirus • adenovirus • (HIV)



•



•



Figure 7.3 Cryptosporidium on electromicrograph. Development stages of cryptosporidium on the surface of enterocytes (note microvilli). The cryptosporidia are surrounded by a parasitophorous vacuole, the outer layers of which are derived from host cell outer membranes



Box 7.3 Treatment of HIV-associated diarrhoea

• Specific • antibiotics • antivirals Fluid replacement Antidiarrhoeal agents • loperamide • diphenoxylate • codeine Slow release morphine Subcutaneous diamorphine



• •



Weight loss and anorexia

Weight loss is a major problem in AIDS and directly influences survival. The causes of weight loss are complex and several factors may coexist in individual patients. Anorexia may occur secondary to drug therapy, opportunistic infection, taste disturbance, or oral discomfort, resulting in inadequate food intake. Malabsorption of fat, lactose, vitamin B12, and bile salts has been demonstrated. Simple dietary measures such as encouraging smaller, more frequent, meals may be helpful and a wide variety of nutritional supplements are available. Appetite stimulants such as megestrol acetate may be beneficial but weight gain is usually modest. Recombinant human growth hormone, although expensive, may partially reverse HIV-associated weight loss. In patients unable to tolerate oral feeding, enteral and parenteral feeding are alternative forms of nutrition but their efficacy and place in management are still being evaluated. Enteral nutrition offers a safer and cheaper alternative to total parenteral nutrition which is perhaps most useful in patients with severe diarrhoea, nausea, and vomiting, in whom fluid balance and control of symptoms has been difficult.



• •



Figure 7.4 Cytomegalovirus antigen demonstrated by immunofluorescence microscopy after culturing human fibroblasts with homogenised intestinal tissue



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ABC of AIDS



Hepatitis and cholestasis

Abnormal liver biochemistry and/or hepatomegaly are common clinical problems although frank jaundice is uncommon. With the multiple therapies being used in treatment and prophylaxis, a drug-induced hepatitis must always be considered in a patient with AIDS and abnormal liver function tests. The differential diagnosis is wide and may involve the use of serology, abdominal ultrasound, ERCP, and liver biopsy. These latter two diagnostic procedures are clearly invasive and would not be indicated unless treatment of opportunistic infection, malignancy or biliary strictures was contemplated. In the absence of dilatated bile ducts on ultrasound, liver biopsy usually shows a granulomatous hepatitis caused by atypical mycobacteria. AIDS sclerosing cholangitis presents with right upper quadrant pain, accompanied by a raised alkaline phosphatase. Abdominal ultrasound is abnormal in the majority of patients with biliary tract dilatation. ERCP may demonstrate papillary stenosis, dilatation of the common bile duct and dilatations and strictures with “beading” of the intrahepatic ducts. The disease is commonly associated with cryptosporidiosis, microsporidiosis, or cytomegalovirus infection. Endoscopic sphincterotomy may give pain relief in a proportion of patients with papillary stenosis. Liver function tests do not usually improve, and as it is a late-stage manifestation, the prognosis is poor, with most patients dying from some other HIV-related complication within six months of diagnosis. HIV infection may alter the natural history of hepatitis B infection in a number of ways. The response rate to hepatitis B vaccination is lower in HIV-infected recipients. Immunodeficiency may favour the establishment of chronic infection following acute infection and HBV replication is increased with a reduction in the rate of spontaneous loss of HBe antigen. Interferon therapy would appear to be less effective in chronic HBV/HIV dual infection. The immune restoration following the initiation of antiretroviral therapy may lead to a hepatitis “flare” in chronic HBV carriers. Hepatitis C virus infection is found primarily in intravenous drug users, although it may also be sexually transmitted. HIV can modify the natural history of HCV infection and patients with HIV/HCV dual infection tend to have more aggressive liver disease.



Figure 7.5 ERCP of AIDS sclerosing cholangitis with intrahepatic biliary tract distortion and dilatation of the common bile duct



Box 7.4 Differential diagnosis of liver disease

• Hepatitis or cholestasis • M. avium-intracellulare complex • Drug-induced • Viral hepatitis • Cytomegalovirus • Mycobacterium tuberculosis • Cryptococcus • Microsporidia • Lymphoma • Kaposi’s sarcoma Biliary disease • Cryptosporidium • Cytomegalovirus • Microsporidia • Lymphoma • Kaposi’s sarcoma



•



Anorectal disease

Perianal discomfort is often caused by recurrent herpes simplex infection. The diagnosis should be confirmed by viral culture. Patient-initiated intermittent aciclovir can give adequate symptom control in some cases but many patients will require long-term maintenance therapy. Resistance to both aciclovir and ganciclovir has been reported. Foscarnet is then the treatment of choice. Anal warts are common but rarely cause much in the way of symptoms and should be treated on merit given the absence of any effective antiviral therapy. Anal intraepithelial neoplasia has been described in association with human papillomavirus infection but reports of invasive malignancy are still infrequent. Patients may present with a mucopurulent proctitis, possible causes of which include recently acquired or long-standing Neisseria gonorrhoeae or Chlamydia trachomatis infection.



Figure 7.6 Aciclovir-resistant perianal herpes simplex infection



40



Gastrointestinal and hepatic manifestations



Neoplasia

Kaposi’s sarcoma (KS) is commonly seen in the gastrointestinal tract and occurs in homosexual men more frequently than in patients from other risk groups. A new human herpes virus (HHV8) or Kaposi’s sarcoma-associated herpes virus (KSHV) has been recently identified as a likely aetiological agent. KS lesions in the gut have the range seen in the skin, from small telangiectatic lesions, not well shown on contrast studies and only seen at endoscopy, to larger nodular or polypoid lesions. Complications from gastrointestinal disease are unusual, but include ulceration, obstruction, haemorrhage, and diarrhoea. Lymphoma is much less common than KS however, although the incidence of KS has decreased along with the incidence of life-threatening opportunistic infections in association with the introduction of highly active antiretroviral therapy. The incidence of lymphoma has not been affected. HIV-associated lymphomas are usually high grade nonHodgkin’s type, of B-cell origin. Extranodal involvement is typical and the gut is one of the commonest sites involved. We thank Dr Wilfred Weinstein, UCLA Medical School, Los Angeles for providing the photograph of oesophageal candidiasis and Dr David Casemore, PHLS Glan Clwyd, North Wales for the electronmicrograph of cryptosporidium.



Figure 7.7 Discrete lesion of Kaposi’s sarcoma in the rectum



41



8



Neurological manifestations



Hadi Manji



In patients infected with HIV, the whole neuraxis is vulnerable to damage. Up to 10% of patients may present with a neurological disorder at seroconversion (Box 8.1). The aseptic meningoencephalitis, which is usually self limiting, presents with headache, meningism, cranial nerve palsies and seizures. An acute demyelinating polyradiculoneuropathy (Guillain–Barré syndrome) is identical to that found in non-HIV-infected individuals, clinically and in the response to treatment with intravenous immunoglobulin or plasmapharesis. However, the cerebrospinal fluid shows a pleocytosis of over 20 cells/mm 3 which is unusual in non HIV cases. A high index of suspicion is required and HIV should be considered in all such cases. During the asymptomatic phase of the illness, which may be of variable duration, headache and cranial nerve palsies (especially VIIth nerve – Bell’s palsy) may be the only manifestation of a low-grade chronic meningitis. The opportunistic infections and tumours as well as the complications ascribed to HIV itself usually develops when the CD4 count drops below 200/mm 3 (Box 8.2). Since the introduction of HAART, there has been a significant reduction in the incidence of infections such as toxoplasmosis and CMV.



Box 8.1 Seroconversion neurological presentations

• • • • • • Encephalitis Aseptic meningitis Myelitis Cauda equina syndrome Acute demyelinating neuropathy (Guillain–Barré syndrome) Myositis



Box 8.2 Neurological complications in HIV infection

Opportunistic infections • Toxoplasma gondii – abcesses and encephalitis • Cryptococcus neoformans – meningitis • JC virus – leucoencephalopathy (PML) • CMV – retinitis, encephalitis, cauda equina syndrome, mononeuritis multiplex Tumours • Primary CNS lymphoma HIV-related disorders • HIV-associated dementia complex • Vacuolar myelopathy • Peripheral neuropathy (distal sensory polyneuropathy) • Polymyositis



Clinical approach

The CD4 count is a useful guide to the aetiology of a neurological presentation – toxoplasmosis and cryptococcal meningitis occur at CD4 counts below 200/mm 3 whereas CMV complications occur below 50/mm 3. Since HIV infection itself results in CSF abnormalities such as a raised white cell count and an elevated protein level, more specific tests are required to diagnose encephalitic and meningitic illnesses. These include the measurement of cryptococcal antigen levels in cases of meningitis due to C. neoformans and CSF–VDRL and TPHA if syphilis is a differential. The inflammatory response is impaired and patients with meningitis may present with only mild symptoms of headache and no neck stiffness or photophobia. The threshold for investigating with CT/MRI and lumbar puncture is necessarily low. The measurement of serum antibodies to diagnose, for example toxoplasmosis, is unhelpful since the usual rise in levels of IgM does not occur. Infection with more than one organism occurs not infrequently, for example Cryptococcus neoformans and Mycobacterium tuberculosis and needs to be considered in cases of non-response or deterioration.



Focal signs, seizures, headache, altered mental status



CT/MRI*



Multiple lesions



Single lesion



RX as toxoplasmosis#



Toxoplasma serology



response



Box 8.3 Clinical guidelines

• • • • • • CD4 useful guide to aetiology Persistent CSF abnormalities due to HIV Reduced inflammatory response Impaired antibody response Multiple simultaneous infections Maintenance treatment required



Continue for six weeks



BIOPSY

Figure 8.1 Management of mass lesions in HIV infection. * MRI is preferred mode of imaging. # If significant mass effect treat with reducing course of dexamethasone in addition to toxoplasma therapy



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Neurological manifestations



Opportunistic infections

Toxoplasma gondii Toxoplasmsosis in HIV infection is usually a reactivation of latent infection in individuals who have been exposed previously to the organism. The clinical presentation is with headache with rapidly evolving focal neurological deficits over one to two weeks which include hemiparesis, dysphasia, visual field deficits, movement disorders (chorea/athetosis, parkinsonism) and seizures. Rarely, toxoplasmosis may affect the spinal cord and present with a myelopathy or a cauda equina syndrome. Blood serology for T. gondii is only helpful if negative since this makes the diagnosis less likely. Patients should have their toxoplasma serology documented at the first diagnosis of HIV infection. The risk of developing toxoplasma encephalitis in IgG seropositive patients is between 12% and 30%. These patients should be offered primary prophylaxis with co-trimoxazole at CD4 counts below 200. CT/MRI shows multiple enhancing lesions with mass effect in the region of the basal ganglia and at the grey/white interface. A response to treatment is seen in 85% by day 7 and in over 90% by day 14. Repeat imaging should be performed after two weeks even if there is clinical improvement in cases of mixed pathology. In patients with significant mass effect and cerebral oedema who are in danger of coning, additional treatment with dexamethasone will be necessary. A deterioration after this has been tailed off makes it necessary to consider a biopsy. Cryptococcus neoformans C. neoformans is a ubiquitous organism acquired by inhalation. Patients with meningitis may present acutely or insidiously over days or weeks with a headache, general malaise, confusion or seizures. The classical signs of meningism – neck stiffness, photophobia and Kernig’s sign – are frequently absent. Brain imaging is usually normal but MRI may reveal small abcesses – cryptococomas. The CSF cell count and protein may be normal and the diagnosis is confirmed by the presence of cryptococcal antigen in the CSF in 95% of cases. India ink staining is positive in 75%. 85% of cases are culture positive – the gold standard. Measurement of the serum cryptococccal antigen is a useful screening tool in patients presenting with headache or fever but should not be considered definitive. Intracranial hypertension in the absence of mass lesions or hydrocephalus is an important cause of mortality and visual failure in approximately 20%. This is managed by repeated lumbar punctures or by the insertion of a lumbar or ventricular drain. JC virus Progressive multifocal leucoencephalopathy (PML) results from reactivation of the JC virus in immunosuppressed individuals. 80% of the general population will have been exposed to this virus as a banal childhood upper respiratory infection and have positive serology. The presentation is with slowly evolving focal neurological deficits such as a hemiparesis, visual field and language problems and incoordination due to cerebellar involvement. Occasionally patients develop a dementia in association with these focal abnormalities. Symptoms and signs of raised intracranial pressure are absent although headache may be a feature. Blood serological testing is unhelpful. Cranial CT shows non-enhancing areas of low attenuation in the white matter. MRI shows characteristic scalloping abnormalities at the grey/white interface with no mass effect or enhancement. The diagnosis may be confirmed by isolating JC virus by polymerase



Box 8.4 Focal lesions in AIDS

• • • • Toxoplasmosis Primary CNS lymphoma Tuberculoma PML



Figure 8.2 T 2 -weighted MRI scan showing multiple rounded or oval abscesses before treatment in cerebral toxoplasmosis



Box 8.5 Meningitis in HIV infection

Fungal • Cryptococcus neoformans Bacterial • Mycobacterium tuberculosis • Listeria monocytogenes • Streptococcus pneumoniae • Treponema pallidum Viral • HIV • Herpes simplex, herpes varicella zoster



Box 8.6 Poor prognostic features of AIDS-related cryptococcal meningitis

• • • • • Relapse episode CSF cryptococcal Ag titre 1:10 000 Positive India ink preparation Hyponatraemia Culture of extrameningeal cryptococcus



Figure 8.3 T 2 -weighted MRI scan showing large area of high signal in one hemispheric white matter with no mass effect. Biopsy proved progressive multifocal leukoencephalopathy



43



ABC of AIDS

chain reaction (PCR) techniques in the CSF in 75% of cases. If this is negative, a brain biopsy may need to be performed. This typically shows areas of focal demyelination, bizzare enlarged astrocytes and abnormal oligodendrocytes with inclusions which stain for JC viral antigens. There is at present no specific treatment for PML. Cytosine arabinoside has been shown to be ineffective but trials are underway looking at the efficacy of drugs such as cidofovir (an anti CMV drug) and alpha interferon. Improvement in immune function with HAART has resulted in significantly better survival times. Cytomegalovirus Over 90% of HIV-infected individuals have serological evidence of CMV infection. The neurological complications, which occur at CD4 counts below 50/mm 3, include retinitis, a cauda equina syndrome, an encephalitis and a mononeuritis multiplex. Apart from retinitis, the other complications occur infrequently. CMV retinitis The initial presentation of CMV retinitis depends upon the location – patients may be asymptomatic, complain of floaters, lose peripheral vision or if the lesions are centred around the macula, have poor visual acuity. Patients will often have evidence of CMV disease elsewhere such as colitis and such patients need to be screened for retinitis regularly. On fundoscopy, there is a perivascular yellow-white infiltrate with retinal haemorrages. The differential diagnosis includes retinal complications of toxoplasmosis, lymphoma, syphilis, herpes zoster and herpes simplex. CMV polyradiculopathy This well-recognised syndrome presents over a period of days with back pain followed by the development of a progressive flaccid weakness of the legs with sensory loss and sphincter disturbance. Imaging studies which are essential to exclude compressive lesions due to, for example, lymphoma are normal or may show thickened nerve roots. The CSF shows a characteristic neutrophil pleocytosis which is unusual in a viral infection. Without treatment there is a progression of the neurological deficits, with death in 2 or 3 months. CMV encephalitis Although evidence of CMV infection is often found in the brains of patients dying from AIDS, the clinical correlates are unclear. A CMV encephalitis needs to be considered in patients presenting with a rapidly progressive encephalitis with cranial nerve palsies and seizures. CMV may be isolated from the CSF using PCR. Box 8.7 Clinical signs and symtoms in PML

• • • • • • • Motor function abnormalities (including hemiparesis) Mental status charges VIIth cranial nerve palsy Cerebellar syndrome Language disorders (dysphasia) Visual problems (for example hemianopia) Seizures



Figure 8.4 Haemorrhagic retinitis due to cytomegalovirus



Primary CNS lymphoma (PCNSL)

PCNSL is the most common cause of mass lesions in children and the second most common in adults after toxoplasmosis. Histologically, this is a high-grade B cell lymphoma. The Ebstein–Barr virus can be isolated from tissue specimens and is believed to have a causal role in the development of the lymphoma. The clinical presentation is similar to that of toxoplasmosis with focal neurological deficits such as hemiparesis and seizures. There are usually signs and symptoms of raised intracranial pressure with increasing headache, vomiting and papilloedema. Although the isolation of EBV by PCR in the CSF is specific, most patients present with mass lesions and raised intracranial pressure. Lumbar puncture is therefore contraindicated. The CT and MRI findings may be 44



Figure 8.5 Enhancing right frontal mass lesion due to lymphoma



Neurological manifestations

indistinguishable from those due to toxoplasmosis with multiple enhancing lesions with associated cerebral oedema and mass effect. However, a single lesion on MRI especially if the toxoplasma serology is negative, is more likely to be lymphoma, as are lesions which closely adhere to the ventricular walls. The diagnosis of PCNSL is usually made by biopsy.This may be performed after failure of treatment with antitoxoplasma therapy for at least two weeks. However, since prognosis is poor even with whole brain radiotherapy, it is reasonable not to proceed with a biopsy unless there is a suspicion that other more treatable pathogies may be identified. Box 8.8 Symptoms and signs of HIV dementia

Early • Poor concentration • Forgetfulness • Clumsiness • Unsteady gait • Apathy • Impaired eye movements • Brisk reflexes • Slowed fine finger movements Late • Global dementia • Incontinent of urine and faeces • Seizures • Spastic paraparesis (due to vacuolar myelopathy) • Myoclonus



HIV-associated dementia complex (AIDS dementia complex) or HIV dementia

This complication occurs in 15% of AIDS patients usually in patients with a CD4 count below 200/mm 3. The early reports of evidence of cognitive abnormalities in HIV positive asymptomatic individuals have been discounted by large cohort studies using clinical, neuropsychological, MRI and neurophysiological methods of assessment. The clinical picture is of a variably progressive dementia with psychomotor slowing and impairment of memory. The diagnosis is one of exclusion of other infective or neoplastic aetiologies by brain imaging and CSF examination. Although there is a correlation between the CSF HIV RNA viral load and the severity of dementia, there is too much overlap for use as a diagnostic test. A neuropsychological assessment is also helpful. MRI shows cortical atrophy and diffuse or patchy white matter high signal on T2-weighted images. The underlying pathophysiological mechanisms are unclear but HIV is usually isolated from the microglial cells and astrocytes rather than neuronal cells. Productive infection of the macrophages and microglia with the release of cytokines such as TNF results in neuronal damage. Since the introduction of zidovudine and subsequently HAART the incidence of HIV-associated dementia has progressively declined. However, more recently there is concern that the CNS may become a sanctuary for HIV, since most of the newer drugs penetrate the CNS poorly.



Figure 8.6 T 2 -weighted MRI scan showing “milky” hyperintensity of the hemispheric white matter due to HIV dementia



Box 8.9 Peripheral nerve disorders in HIV infection

HIV related • Axonal neuropathy (distal sensory peripheral neuropathy, DSPN) • Demyelinating neuropathy – acute (Guillain-Barré syndrome), chronic (CIDP) • Vasculitic neuropathy (mononeuritis multiplex) • Diffuse infiltrative lymphocytic syndrome (DILS) CMV related • Vasculitis (mononeuritis multiplex) • Lumbosacral polyradiculopathy Toxic • ddl, ddC, D4T • isoniazid • thalidomide • dapsone



Peripheral nerve disorders in HIV infection

DSPN is the commonest neurological complication encountered in HIV patients, with 30% of AIDS individuals experiencing symptoms. It is unusual in the asymptomatic stages of HIV infection. Pathologically, this is a length-dependent axonal neuropathy usually sparing the hands. The symptoms and signs are typical of a small fibre neuropathy. Treatment is symptomatic using antidepressant and anticonvulsant drugs. The neuropathy due to the nucleoside analogue drugs (ddl, ddC and D4T) is similar and therefore difficult to differentiate from DSPN. These drug related neuropathies are dose dependent and reversible. However, patients may continue to deteriorate for 6–8 weeks after stopping the drug – “coasting”.



Box 8.11 Investigations in HIV neuropathy Box 8.10 Symptoms and signs of DSPN

• • • • • • Numb, burning feet Pins and needles Contact hypersensitivity Little or no weakness Impaired pain and temperature sensation Depressed or absent ankle jerks • • • • • Neurotoxic drugs, including excess vitamin B 6 Excess alcohol Blood tests: vitamin B 12, glucose, VDRL, vitamin E (if severe diahorrea) Nerve conduction tests – only if marked weakness or unusual presentation Nerve biopsy may be indicated to exclude an inflammatory neuropathy (vasculitis or demyelination)



45



9



Treatment of infections and antiviral therapy



Ian VD Weller, IG Williams



The treatment of HIV infection can be largely divided into: (i) specific antiviral agents that inhibit viral replication, (ii) measures that either treat or prevent (prophylaxis) its complications – namely opportunistic infections and tumours. Major advances in the treatment of HIV infection have occurred in the last few years. This has resulted in marked falls in the reported number of new AIDS cases and deaths in the developed world since 1996. Effective antiretroviral therapy regimens which substantially inhibit HIV replication and allow sustained improvements in the immune system are the main reason for this. There are currently three classes of antiretroviral agents: the nucleoside and non-nucleoside reverse transcriptase inhibitors and the protease inhibitors. Improved formulations and new drugs are continuously being evaluated and there is increasing interest in the possible role of immunotherapy combined with antiretroviral therapy to improve specific immune responses. However, in those who are severely immunosuppressed the treatment and prophylaxis of opportunistic infections remains important. Though it cannot be overemphasised that the most effective way to prevent first episodes or recurrences of opportunistic infections is treatment with antiretroviral drugs. This chapter will cover both antiretroviral therapy and the treatments of the infections previously described in other parts of this book, in an attempt to bring all of these together in a comprehensive manner.



Box 9.1 Treatment strategies in HIV disease

• • • Antiretroviral therapy: suppresses viral replication results in immune reconstitution Prophylaxis of opportunistic infections Prevent exposure to opportunistic pathogens



Protozoal infections

Pneumocystis carinii pneumonia (PCP) Although recently recognised as being more like a fungus, P. carinii is considered under protozoa here. Nowadays PCP most commonly occurs in those at risk who fail to take adequate prophylaxis or who are newly diagnosed with HIV infection in advanced disease where it is frequently the presenting illness. Clinical suspicion is aroused early in patients who are under regular medical supervision, leading to earlier diagnosis. Later diagnosis is asssociated with more severe disease and poorer treatment outcome. Techniques of diagnosis include sputum induction with nebulised saline; this obviates the need for bronchoscopy but the diagnostic sensitivity is lower. The use of lavage alone at bronchoscopy avoids transbronchial biopsy with its complications of haemorrhage and pneumothorax. Exercise oximetry and alternative imaging techniques with radiolabelled compounds are also being used in diagnosis. Monoclonal antibodies to pneumocystis proteins and sensitive DNA probes have been developed but have yet to reach the bedside. In the absence of a confirmatory test, a presumptive diagnosis may be made based on the clinical presentation and chest x ray appearances in a patient severely immunosuppressed and at risk. High-dose intravenous co-trimoxazole for two to three weeks remains a standard first-choice regimen for severe PCP, but once fevers and symptoms have settled and blood gas values have improved the drug can be given by mouth. Side-effects are common, typically after 7–10 days. If co-trimoxazole treatment is not tolerated, alternative treatment regimens include either intravenous pentamidine or a combination of clindamycin and primaquine. Pentamidine is as effective as co-trimoxazole but has side-effects that can be life threatening and should be given 46



Figure 9.1 Chest x ray appearance of Pneumocystis carinii pneumonia showing interstitial infiltrates



Treatment of infections and antiviral therapy

by slow intravenous infusion with careful monitoring. In patients with moderate or mild PCP a combination of clindamycin and primaquine has proven clinical efficacy and is an alternative first choice for those patients who have a previous history of severe co-trimoxazole hypersensitivity. Side-effects of rash and diarrhoea are frequent. In patients presenting with severe hypoxaemia high-dose adjunctive corticosteroid therapy is indicated and has been shown in clinical studies to reduce both mortality and morbidity Alternative second-line therapies include dapsone with trimethoprim, trimetrexate with folinic acid or Atovaquone, a hydroxy-naphthoquinone. The efficacy of atovaquone has only been established in mild to moderate P. carinii infection. Like trimetrexate it is probably less effective than co-trimoxazole but it is less toxic. New formulations have improved atovaquone’s bioavailability but it still should not be given to patients with malabsorbtion conditions, previous severe diarrhoea or those not taking oral nutrition. Due to acquired resistance, where possible atovaquone should not be given as single-agent therapy. It is commonly combined with intravenous pentamidine as an effective second-line treatment. Prophylaxis for PCP pneumonia is essential after a first attack (secondary prophylaxis) but is also recommended for all patients once their CD4 cell counts falls below 200 10 6/l (primary prophylaxis). The risk of a first episode PCP below this CD4 count level in patients not on antiretroviral therapy is estimated to be 18% at 12 months for those who are asymptomatic, rising to 44% for those who have early symptomatic disease (for example, oral candida, fever). Cotrimoxazole 960 mg given by mouth daily or three times per week is the most effective agent. In patients who are intolerant, alternative regimens include oral dapsone 100 mg with pyrimethamine 25 mg daily or three times per week, atovaquone 1500 mg daily or nebulised pentamidine. Dose of the latter depends on the nebuliser system: with a Respirgard II nebuliser the recommended regimen is 300 mg every four weeks. In patients with more advanced disease and CD4 counts less than 100 10 6/l, 300 mg given every two weeks should be considered in view of the high failure rate of the monthly regimen.



Figure 9.2 Cysts of Pneumocystis carinii in broncho lavage specimen



Table 9.l Pneumocystis carinii pneumonia treatment

Drug First choice: Co-trimoxazole (trimethoprim component 15–20 mg/kg per day p.o./i.v. in divided doses). Alternative regimens: 1. Severe disease: Pentamidine isethionate 4 mg/kg per day as slow intravenous infusion Trimetrexate 45 mg/m 2 i.v. and folinic acid 80 mg/m 2 2. Mild to moderate disease: Clindamycin 600 mg 6 hourly p.o./i.v. and primaquine 15 mg daily p.o. Trimethoprim 20 mg per kg/day p.o./i.v. in 2–3 divided doses and dapsone 100 mg daily p.o. Atovaquone suspension 750 mg twice daily Duration Side-effects 21 days Nausea, vomiting, fever, rash, marrow suppression, raised transaminases Hypotension, hyper- and hypoglycaemia, renal failure, marrow suppression, nausea, vomiting, cardiac arrest Marrow suppression, raised transaminases rash, anaphylaxis Diarrhoea, rash, nausea, vomiting, marrow suppression, methaemoglobinaemia, haemolysis Rash, nausea, methaemoglobinaemia, marrow suppression Rash, raised transaminases and neutropenia Comments Intolerance common (25–50% of treated patients)



21 days



80% of patients will respond to treatment



21 days 21 days



Should only be used as third or fourth line treatment Clostridium difficile toxin associated diarrhoea is a frequent complication of clindamycin therapy



21 days



Alternative regimens should be used in patients with G6PD deficiency Must be taken with food. Consider combination with i.v. pantamidine as resistance reported with monotherapy Indicated in severe disease. Optimal dose not determined



21 days



Adjuvant high-dose steroids 5 days (for example, prednisolone 40–60 mg daily p.o.)



tapering over 14–21 days



47



ABC of AIDS

Although clinical trials have shown greater efficacy for cotrimoxazole compared to other regimens, there is a high rate of discontinuation due to side-effects. Desensitisation regimens are used with the aim of reducing the rate of intolerance but there is uncertainty about their efficacy and which regimen is best. In patients responding to antiretroviral therapy, primary or secondary prophylaxis can be safely discontinued once the CD4 count has increased to levels persistently above 200 10 6/l. Toxoplasmosis Cerebral toxoplasmosis is the commonest manifestation of toxoplasma infection. As toxoplasmosis is the most common cause of ring-enhancing lesions on contrast CT brain scans a presumptive diagnosis is usually made and treatment started. The condition responds well if treatment is started early, and a combination of sulphadiazine 4–6 g/day and pyrimethamine 50–100 mg a day (both by mouth in divided doses with folinic acid 15 mg daily) is the treatment of choice. Side-effects may prevent continued use of sulphadiazine, and clindamycin 600–1200 mg four times a day has been shown to be an effective alternative in controlled studies. Corticosteroids are sometimes used in addition to first-line treatment to reduce symptomatic cerebral oedema, but a clinical and radiological response seen after two weeks of treatment may be due solely to the corticosteroid effect rather than the anti-toxoplasma treatment. A presumptive diagnosis of toxoplasma may therefore be made, although the underlying lesion may be due to something else, such as lymphoma or another infection. Relapse is common after treatment is stopped, and maintenance treatment is therefore necessary. In patients responding to antiretroviral therapy with sustained increases in CD4 count, discontinuation of prophylaxis is safe but there is limited current data to make definite recommendations. Atovaquone 750 mg four times a day with or without pyrimethamine may be considered an alternative and the new macrolides clarithromycin 2 g daily and azithromycin, both given with pyrimethamine 75 mg/day, have also been effective in small uncontrolled studies. The most appropriate regimen for secondary prophylaxis has not been determined but treatment doses of either sulphadiazine and pyrimethamine or clindamycin and pyrimethamine are usually halved. Of patients with positive toxoplasma serology and a CD4 count of less than 100 10 6/l, approximately 1 in 3 will develop cerebral toxoplasmosis within 12 month without prophylaxis. Primary prophylaxis in patients with positive serology with a CD4 count of less than 100 10 6/l is therefore recommended. Co-trimoxazole or dapsone with pyrimethamine have been shown to reduce the incidence of toxoplasmosis compared to patients taking nebulised pentamidine for prophylaxis against PCP. Atovaquone with or without pryrimethamine may also be considered but this is based on more limited data. The macrolides clarithromycin and azithromycin might be anticipated to provide broad-spectrum prophylaxis for toxoplasmosis, atypical mycobacterial and bacterial infections, but bacterial resistance might limit their use in this situation. Patients who are toxoplasma serology negative should be given advice to prevent exposure in primary infection with toxoplasmosis. They should be advised not to eat raw or undercooked meat and avoid directly handling cats’ faeces. Cryptosporidiosis and other protozoa In patients with less advanced HIV disease (CD4 counts >200 10 6/l) cryptosporridial infection usually causes a self-limiting gastrointestinal illness and symptomatic treatment with 48



Figure 9.3 CT scan showing ring-enhancing lesions of cerebral toxoplasmosis surrounded by cerebral oedema (dark area)



Box 9.2 Treatment of toxoplasmosis

First line Sulphadiazine 4–6 g per day or clindamycin 600–1200 mg per day Pyrimethamine 50–100 mg per day Folinic acid 15 mg per day Alternatives • Clarithromycin 2 g per day or • Atovaquone 750 mgs 4 per day p.o. Pyrimethamine 50–100 mg per day p.o. 4



Figure 9.4 Cryptosporridial infection of the small bowel



Treatment of infections and antiviral therapy

anti-diarrhoeal agents is all that maybe needed. In those with more severe immunosuppression and persistent symptoms treatment is more difficult and reported successes with a variety of agents are still anecdotal. Symptoms and excretion of cysts may be intermittent. Responses have been described after treatment with a variety of agents, including spiramycin, erythromycin, diclazuril, letrazuril, hyperimmune bovine colostrum, paromamycin, azithromycin and subcutaneous somatostatin. Symptomatic treatment with antidiarrhoeal and antiemetic agents together with fluid, electrolyte and nutritional support should be provided. Case reports suggest that immune reconstitution is likely to result in improvement and resolution of both symptoms and infection. Thus in the absence of an effective specific treatment against cryptosporidium, infected patients should be started on antiretroviral therapy to increase the CD4 count. Patients at risk of infection should be advised to avoid possible exposure in water supplies particularly at times of documented outbreaks. Although unproven, measures that may be considered for patients with CD4 counts less than 200 10 6/l include using bottled water, point of use filters or boiling water for more than one minute. For microsporidiosis there have been anecdotal reports of symptomatic improvement with albendazole 400 mg twice a day or metronidazole 500 mg three times a day. Isosporiasis is less common and appears to respond to cotrimoxazole 960 mg four times a day, but relapses occur in half of all cases. Diarrhoea often occurs in the absence of recognised pathogens in the stool, and metronidazole has relieved symptoms in some cases.



Figure 9.5 Cryptosporidium



Table 9.2 Viral opportunistic infections

Infection Herpes simplex Treatment Drug Duration Side-effects Comments Duration may be extended in severe infections



Prophylaxis Cytomegalovirus Treatment



Aciclovir 200 mg 5 a day 5–7 days orally or 10 mg/kg 8 hourly i.v. Aciclovir 200 mg 4 a day Indefinite or 400 mg 2 x day Ganciclovir 5 mg/kg twice a day i.v. Cidofovir 5 mg/kg i.v. once a week 14-21 days 2 weeks Neutropenia, anaemia



GCSF support may be required



Foscarnet 180 mg/kg daily i.v.



Maintenance ganciclovir



Ganciclovir 3 gr daily orally



Cidofovir 5 mg/kg once every 2 weeks



Nephrotoxicity: impaired Co-administer with probenecid and creatine clearance, proteinuria, adequate hydration to reduce risk of hypophosphataemia nephrotoxicity Neutropenia Ocular toxicity 14–21 days Nephrotoxicity, hypomagnesaemia, Dose must be adjusted according to hyper- and hypocalcaemia, hyperrenal function and hypophosphataemia, hypokalaemia, nausea vomiting, genital ulceration Until CD4 As above May be combined with intraoccular count > implants Avoid in patients with diarrhoea 100 10 6/l on HAART Increases levels of didanosine Until CD4 As above As above count > 100 10 6/l on HAART



Alternative secondary prophylaxis regimens include daily intravenous foscarnet or ganciclovir, intravitreal injections of ganciclovir or foscarnet and intraoccular ganciclovir implants



49



ABC of AIDS



Viral infections

Severe mucocutaneous and systemic infections with herpes simplex virus are best treated with aciclovir. Prophylaxis is used after severe infection and in patients with increasing severity and frequency of recurrences. These recurrences can be a prelude to the chronic persistent mucocutaneous ulceration characteristic of AIDS. Varicella zoster virus infections are usually treated with high-dose aciclovir given by mouth. However, dissemination of infection from dermatomal zoster is unusual even without treatment. Valaciclovir is a pro-drug of aciclovir which is used in the treatment of herpes zoster and herpes simplex infections of skin and mucous membranes. Valaciclovir is a L -valine ester of aciclovir that is rapidly converted to aciclovir after oral administration. The antiviral spectrum and mode of action is therefore the same as aciclovir. Aciclovir has, however, a low oral bioavailability (about 15–20%). Valaciclovir has three or four times the oral bioavailability of aciclovir. Famciclovir is a diacetyl ester of 6-deoxy penciclovir which has been used in the treatment of herpes zoster and genital herpes infections. Famciclovir is metabolised to penciclovir in the intestinal wall and liver. Penciclovir and aciclovir have similar antiviral spectrum. Aciclovir resistant herpes simplex infections can occur, particularly in patients with advanced disease and severe immunosuppression. Alternative agents to treat resistant infections include foscarnet and cidofovir. Reactivation of cytomegalovirus with viraemia and endorgan disease tends to occur when CD4 cell counts are persistently below 50 10 6/l. Ganciclovir (an acyclic analogue of deoxyguanosine), foscarnet phosphonoformate (a pyrophosphate analogue, which inhibits polymerase enzymes) and cidofovir (a nucleoside analogue with potent in vitro activity against viruses) are used for the treatment of cytomegalovirus retinopathy, gastrointestinal and neurological disease. Treatment arrests progression retinitis in most patients, and maintenance therapy is required in those patients who continue to be severely immunosuppressed to delay the time to further relapse. There is little comparative data to guide initial choice of treatment. A study comparing ganciclovir with foscarnet for treatment of CMV retinitis found no difference between the drugs in their ability to delay progression of disease, but there was a survival advantage in those patients treated with foscarnet. However, foscarnet is not as well tolerated as ganciclovir, as it produces reversible renal failure and electrolyte disturbances. Careful and frequent monitoring is required which complicates outpatient management. The major side-effect of ganciclovir is bone marrow suppression, particularly neuropenia. Support therapy with granulocyte colony simulating factor (GCSF) maybe required. The detection of mutations in the CMV UL97 gene is associated with an increase in CMV DNA levels in blood and clinical progression of CMV retinitis during ganciclovir therapy. High-level resistance to ganciclovir results in cross-resistance to cidofovir. Resistance to foscarnet can occur but the mechanism is different. Cidofovir has been shown to be effective however in delaying progression and time to relapse in patients who have experienced therapy failure on ganciclovir and foscarnet. The dosing schedule of cidovofir is convenient and more suitable to outpatient care than with either intravenous ganciclovir or foscarnet. It is given once weekly (5 mg/kg) for two weeks as induction therapy and then at the same dose every two weeks thereafter as maintenance therapy. The main side-effect is 50



Box 9.3 Management of CMV disease: key points

• Population at highest risk of clinical disease: CD4 350 10 6/l



Consider treatment Treatment should depending upon VL, generally be offered rate of CD4 count decline, symptoms and patient wishes Defer Defer or consider treatment if high VL



(1) BHIVA: British HIV Association Guidelines (March 2001) (2) USDHHS: United States Department of Health and Human Services (February 2001)



Box 9.6 Factors associated with virological treatment failure

• • • • • poor adherence drug intolerance and toxicity drug–drug interactions resulting in sub-optimal drug levels development of genotypic mutations associated with reduced drug susceptibility pharmacological resistance resulting in decreased intracellular drug levels



55



ABC of AIDS

suppression of plasma viral load than those who do not. Few patients experience virological treatment failure as a result of poor antiviral potency. The ability of a patient to adhere to a treatment regimen is important in determining the choice of treatment regimen. The dosing schedule, pill burden, the requirement or not for dietary restrictions, risk of side-effects and patient motivation are important in determining adherence. Other factors which contribute to the initial treatment choice are baseline viral load, resistance profile of the drug, future options for treatment, known efficacy of the treatment regimen, the potential for drug to drug interactions and the presence of drug resistance at baseline. The optimal time to initiate therapy with the current antiretroviral drugs has not been established in clinical studies. CD4 count and plasma viral load are predictors of the estimated risk of progression to AIDS which is a factor in determining when to start treatment. The motivation of a patient to start and adhere to therapy and the known effectiveness of current regimens are also important. Clinical practice across Europe and North America varies, but most clinicans would consider initiating therapy at some point between a CD4 count of 200–500 10 6/l and in all patients who are symptomatic. Even in patients who initiate therapy with CD4 counts of 12 years of age) is considered to have AIDS if at least two of the following major signs are present in combination with at least one of the minor signs listed below, and if these signs are not known to be due to a condition unrelated to HIV infection. Major signs • Weight loss 10% of body weight • Chronic diarrhoea for > 1 month • Prolonged fever for > 1 month (intermittent or constant) Minor signs • Persistent cough for > 1 month* • Generalised pruritic dermatitis • History of herpes zoster • Oropharyngeal candidiasis • Chronic progressive or disseminated herpes simplex infection • Generalised lymphadenopathy

The presence of either generalised Kaposi’s sarcoma or cryptococcal meningitis is sufficient for the diagnosis of AIDS for surveillance purposes.



AIDS case definitions and staging of HIV disease

Case definitions of AIDS for epidemiological surveillance For epidemiological surveillance, a practical case definition of severe HIV-related disease is needed. The Centers for Disease Control (CDC) AIDS surveillance case definition is used in many industrialised countries (see chapter 1), but cannot be used in most developing countries because it requires access to sophisticated laboratory investigations. For this reason, the World Health Organisation (WHO) introduced a clinical case definition that could be used in settings where laboratory facilities are inaccessible (Box 10.1). In 1994, this definition was expanded to incorporate HIV serology (thus increasing specificity) and to take account of revisions of the CDC case definition (Box 10.2). If serological testing is unavailable or inaccessible, the clinical case definition should be used; if serological testing is available, the expanded case definition should be used. Diagnosis and clinical staging of HIV disease in resource poor settings Although advanced HIV disease may be easy to diagnose clinically, it is desirable to have HIV serology on patients with suspected HIV disease, particularly since HIV negative tuberculosis may be clinically indistinguishable from advanced HIV disease. The case definitions in Boxes 10.1 and 10.2 were developed for epidemiological surveillance, and are not intended to be used for clinical staging of patients, for which they are neither sensitive nor specific. In order to estimate prognosis in individual patients, a clinical staging system is more useful than a case definition. Box 10.3 overleaf outlines the WHO proposed staging system for HIV infection and disease, using clinical and laboratory data, which can be used in developing countries. This system categorises patients into four stages based on clinical features of prognostic significance. The stages are interpreted as: Stage 1: asymptomatic infection. Stage 2: early (mild) disease. Stage 3: intermediate (moderate) disease. Stage 4: late (severe) disease. The system can be refined using a laboratory axis: the CD4 count is the most useful laboratory marker for clinical staging, but is rarely available in developing countries. The total lymphocyte count can be used as a surrogate, although this is not ideal. Manifestations of HIV disease are rare at CD4 counts above 500 10 6/l and severe illness and death are rare in patients with counts above 200 10 6/l. Tuberculosis and pneumococcal disease may occur at higher as well as lower CD4 counts. Once patients in developing countries have developed advanced HIV disease, they die with higher CD4 levels than in industrialised countries because of lack of access to high quality medical care; nonetheless, most patients die at the stage of advanced immunodeficiency. 62



*For patients with tuberculosis, persistent cough for >1 month should not be considered as a minor sign. Box 10.2 Expanded WHO case definition for AIDS surveillance For the purposes of AIDS surveillance an adult or adolescent (>12 years of age) is considered to have AIDS if a test for HIV antibody gives a positive result, and one or more of the following conditions are present:

• 10% body weight loss or cachexia, with diarrhoea or fever, or both, intermittent or constant, for at least 1 month, not known to be due to a condition unrelated to HIV infection Cryptococcal meningitis Pulmonary or extrapulmonary tuberculosis Kaposi’s sarcoma Neurological impairment that is sufficient to prevent independent daily activities, not known to be due to a condition unrelated to HIV infection (for example, trauma or cerebrovascular accident) Candidiasis of the oesophagus (which may be presumptively diagnosed based on the presence of oral candidiasis accompanied by dysphagia) Clinically diagnosed life-threatening or recurrent episodes of pneumonia, with or without aetiological confirmation Invasive cervical cancer



• • • •



•



• •



Figure 10.10 Squamous cell carcinoma of the conjunctiva: an unusual cancer, strongly associated with HIV infection. Its incidence has increased markedly in Uganda and Rwanda (courtesy of Dr Keith Waddell)



HIV infection and AIDS in the developing world

Box 10.3 Proposed WHO staging system for HIV infection and disease Clinical staging Patients with HIV infection who are aged 13 years are clinically staged on the basis of the presence of the clinical condition, or performance score, belonging to the highest level

• • • Clinical stage 1: asymptomatic or persistent generalised lymphadenopathy; performance scale 1 (asymptomatic, normal activity) Clinical stage 2: weight loss 10% body weight, unexplained chronic diarrhoea > 1 month, unexplained chronic fever > 1 month, oral candidiasis, oral hairy leukoplakia, pulmonary tuberculosis within the past year, severe bacterial infections; performance scale 3 (bedridden 50% of day during the last month)



•



Clinical/laboratory classification Laboratory axis Lymphocytes ( 10 6/l) A B C >2000 1000–2000 500 200–500 2 upper limit of normal) are suggestive of infection but, for diagnostic purposes, should be supported by at least one other test that detects the virus directly. It is important to realise that absolute CD4 counts are physiologically much higher in infants and young children than in adults (Figures 12.7 and 12.8). All children presumed to be uninfected should be followed until seroreversion is confirmed, and longer term follow-up to ensure normal development until four to five years is advised in children exposed to ART perinatally.



Box 12.3 Centers for Disease Control 1994 revised classification system for HIV infection in children less than 13 years old

Category N: no symptoms Category A: mildly symptomatic • Lymphadenopathy • Hepatomegaly • Splenomegaly • Dermatitis • Parotitis • Recurrent upper respiratory tract infections, sinusitis or otitis media Category B: moderately symptomatic Examples of conditions in clinical category B include: • Anaemia, neutropenia or thrombocytopenia • Bacterial infections: pneumonia, bacteraemia (single episode) • Candidiasis, oropharyngeal • Cardiomyopathy • Diarrhoea, recurrent or chronic • Hepatatis • Herpes stomatitis, recurrent • Lymphoid interstitial pneumonia • Nephropathy • Persistent fever > 1 month • Varicella (persistent or complicated primary chickenpox or shingles) Category C: severely symptomatic Any condition listed in the 1987 surveilllance case definition for AIDS, with the exception of LIP. For example: • Serious bacterial infections, multiple or recurrent • Candidiasis (oesophageal, pulmonary) • Cytomegalovirus disease with onset of symptoms at age >1 month • Cryptosporidiosis or Isosporiasis with diarrhoea persisting 1 month • Encephalopathy • Lymphoma • Mycobacterium tuberculosis disseminated or extrapulmonary • Mycobacterium avium complex or M. kansasii, disseminated • Pneumocystis carinii pneumonia • Progressive multifocal leucoencephalopathy • Toxoplasmosis of the brain with onset at age > 1 month • Wasting syndrome



Natural history and clinical manifestations

As in adults, HIV-infected children present with a spectrum of signs and symptoms reflected in the revised Centre for Disease Control classification system (Box 12.3). The differences between adults and children with HIV disease are summarised (Box 12.4). In the absence of HAART, disease progression is generally faster than in adults, with 15–20% of children



76



HIV infection in children

developing AIDS-defining illnesses by 12 months. This subset of perinatally infected children typically present with PCP at around three to four months of age (Figure 12.8). Progression rates to AIDS in infancy have been shown to be reduced by the use of primary PCP prophylaxis with Septrin from 4 to 6 weeks of age onwards. Approximately 70% of perinatally infected children will have some signs or symptoms by 12 months (Figure 12.14). In the absence of antiretroviral therapy, the median age at which children progress to AIDS is about six years, and 25–30% have died by this age. The median age of death is around nine years. In many cases, the child is the first family member to be diagnosed as HIV infected. Some children, however, do not present until the second decade of life. Disease progression in children in developing countries is more rapid (Figure 12.15). Survival following an AIDS diagnosis has greatly improved over the past 10 years, but even where antiretroviral therapy is available the mortality amongst children with PCP and CMV is appreciable (Figure 12.13). This is yet another reason for antenatal HIV testing which can render PCP in infancy wholly preventable. Children with HIV infection frequently present with signs and symptoms that are common in general paediatrics and are non-specific. The most usual clinical features associated with HIV infection include persistent generalised lymphadenopathy, hepatosplenomegaly, chronic or recurrent diarrhoea, fever, and recurrent otitis or sinusitis. Persistent oral candidiasis, bilateral parotitis or neurological signs are more specific of HIV infection. Herpes zoster (shingles) in childhood is uncommon and suggests a defect in cellular immunity justifying an HIV test in the absence of other explanations. Similarly, thrombocytopenia can be a presenting feature, and HIV should be considered in the differential diagnosis of idiopathic thrombocytopenic purpura. Recurrent and often severe bacterial infections are frequent and include pneumonia, cellulitis, local abscesses, osteomyelitis, septic arthritis and occult bacteraemia. The common causative organisms are similar to those seen in children with hypogammaglobulinaemia and include pneumococci, salmonellae, staphylococci, streptococci and Haemophilus influenzae. This reflects the B-cell defect that accompanies the destruction of the CD4 helper T cells. Children with HIV infection frequently have hypergammaglobulinaemia due to dysregulated polyclonal B-cell activation. The antibodies are generally non-functional. Pulmonary disease is an important cause of morbidity and mortality and may be one of the first manifestations. Lymphoid interstitial pneumonitis (LIP), characterised by multiple foci of proliferating lymphocytes in the lung interstitium, occurs in 20–30% of vertically infected children, but is rare in adults. It presents with persistent bilateral reticulonodular shadowing on chest X-ray (Figure 12.9) and clinical features ranging from asymptomatic to chronic hypoxia. It may be an abnormal response to primary Epstein–Barr virus (EBV) infection. Coinfection with Mycobacterium tuberculosis is an increasing problem in children, and can be difficult to distinguish radiologically from LIP. Clinically a child with bilateral infiltrates due to TB would be highly symptomatic, as opposed to LIP which may be clinically silent. Opportunistic infections, apart from PCP and primary disseminated CMV disease in the subset of children with very rapid disease progression, are usually a late complication of HIV infection and result from severe immunosuppression. The most common are oesophageal candidiasis, multidermatomal varicella zoster, disseminated mycobacterium avium complex (MAC) or CMV infections, cryptosporidiosis, and more rarely, Box 12.4 Differences between children and adults with HIV disease

• More rapid disease progression: 20% of children develop AIDS by 12 months Child may be the first family member to present Higher viral loads at presentation Physiologically higher absolute CD4 counts Growth faltering common (affects height and weight) Encephalopathy presents with developmental delay and hypertonic diplegia Opportunistic pathogens encountered for the first time primary illnesses often more severe than OIs in adults Poor primary responses to childhood infections/immunisations Lymphoid interstitial pneumonitis common Malignancy uncommon (accounts for less than 2% of AIDSdefining presentations in children) More rapid clearance of antiretroviral drugs, requiring higher than adult equivalent doses particularly in very young children



• • • • • • • • •



Figure 12.8 Pneumocystis carinii pneumonia (PCP) in a three month old. Diffuse bilateral ground-glass opacification, tending to confluence in right upper and both lower lobes. Air bronchograms are seen, which imply air space disease which is a late feature of disease. The earliest infiltrates are usually perihilar. The absence of pleural effusion or hilar adenopathy is typical. Less typical presentations include miliary, coin and nodular lesions, lobar consolidation and cavitations



Figure 12.9 Lymphoid interstitial pneumonitis (LIP) in a child aged 12 months. Diffuse, well-circumscribed nodules distributed uniformly throughout both lung fields. May be associated with hilar adenopathy. A radiological spectrum is seen in LIP, ranging from fine linear interstitial infiltrates to large nodules that tend to confluence in the right middle and lingular lobes



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ABC of AIDS

toxoplasmosis. MAC should be considered in any child with advanced disease and unexplained fevers, weight loss and abdominal discomfort. Encephalopathy due to effects of HIV infection on the central nervous system is seen most frequently in the subgroup of children with rapid disease progression. The most common neurological manifestations are hypertonic diplegia, developmental delay (particularly affecting motor skills and expressive language) or acquired microcephaly. Cranial imaging studies may show basal ganglia calcification and cerebral atrophy and MRI scans may show evidence of white matter damage. Seizures are not usually a feature of HIV encephalopathy which does not tend to affect the grey matter. The majority of school age children are attending normal school without requiring additional support in the classroom. Malignancy, such as Kaposi’s sarcoma or lymphoma, is a relatively uncommon feature of paediatric HIV disease, accounting for only 1–2% of AIDS-defining illness in children.



Prognostic markers

The most widely used surrogate markers for predicting disease progression in children, as in adults, are the CD4 values and viral load. Very high viral loads are frequently found in infected children, particularly following perinatal transmission (Figure 12.10). Absolute CD4 counts are physiologically higher in children compared with adults (Figure 12.7). CD4 percentages vary rather less, and according to the CDC classification system can be used across all age ranges; >25% is considered evidence of no immunosuppression, 15–25% moderate and 1 000 000 Patients (no.) 25 69 105 20 35 Deaths (no.) 6 19 34 8 25 % mortality 24 28 32 40 71



Management

The aim of any intervention for HIV-infected children should be to maintain the best possible quality of life for the children as long as possible, with the hope that they will be able to take advantage of potential curative therapy in the future. This inevitably means balancing the potential benefits of new treatments against the need for increased monitoring, possible toxicities and limiting future therapeutic options. As a result of advances in ART, there has been a shift in focus from diagnosing and managing opportunistic infections (OI) to preventing them by restoring and maintaining cellular immunity. For most established opportunistic infections, the best treatment is HAART. Antiretroviral therapy Virus replication in children, as in adults, is occurring at all stages of HIV infection and, as improved drugs and drug combinations become available, treatment is likely to be offered increasingly early. Highly encouraging results have been reported with three or more drug combinations in selected, infected infants, which demonstrate that complete viral suppression and maintenance of entirely normal immune development can be achieved and sustained for at least three years. These observations, and studies of adults treated during primary infection, provide a rationale for early aggressive therapy of infants. 78



*Tested by NASBA RNA QT Amplification system on frozen stored serum (lower limit of detection 4000 copies/ml)



Table 12.5 Association of baseline HIV RNA copy number and CD4 cell percentage with long-term risk of mortality in HIV-infected children

Baseline viral load/ CD4 percentage 100 000 copies/ml 15% 100 000 copies/ml 15% 10 6 RNA copies/ml if age 10 5 if age over 1 year) Infant 25% Low viral load: 30 months



•



•



600 514 500 400 300 200 133 100 30 0 UK Ireland Italy Sweden Ger. Neth. France Switz. Spain 15 33 46 387 1 Pl, no NNRTI >1 PI, no NNRTI Pl NNRTI NNRTI, no PI Only NNRTIs No ART



372



154



Figure 12.11 Antiretroviral therapy being received in 1999 by 1694 HIV infected children from paediatric centres in 9 countries, involved in the PENTA network of trials (unpublished data, Paediatric European Network for the Treatment of AIDS)



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ABC of AIDS

Prophylactic measures Early-onset PCP is a preventable disease (Table 12.2). Infants at higher risk of acquiring HIV, whose mothers are identified during pregnancy, can be started on PCP prophylaxis from around 4 to 6 weeks of age onwards. Prophylaxis can be stopped once it has been established that the baby is uninfected. Infected children should continue on prophylaxis throughout the first year of life, as CD4 counts are unreliable indicators of risk (see Figure 12.7). Thereafter, it is not unreasonable to stop prophylaxis for children with CD4 counts consistently above 15%, provided the family are reliable clinic attendees and the child’s clinical status and immune function can be regularly monitored. Any child with rapidly declining CD4 counts or counts consistently less than 15% should be on prophylaxis. Co-trimoxazole is the drug of choice. Regimens vary, but one convenient dosage regimen is suggested in Table 12.5. Rashes and bone marrow suppression due to co-trimoxazole may require switching to alternative prophylactic agents such as dapsone. Routine active immunisation schedules should be followed for HIV-infected or -exposed infants, with the exception that BCG should not be given to symptomatic infected children because of the risk of dissemination. There is a theoretical risk of paralytic poliomyelitis in immunocompromised contacts of children excreting live polio vaccine virus. Inactivated polio vaccine (IPV) may be recommended by injection instead of the live oral polio vaccine. In practice it can be difficult to obtain supplies of IPV in the UK, and in view of the very low transmission rate of HIV, many units now condone giving oral polio vaccine (OPV), and advise carers about thorough handwashing when changing nappies. Pneumococcal polysaccharide vaccine has been recommended for HIV-infected children over two years of age, but is likely to be superseded soon by conjugate vaccines which can be given to younger children. Influenza vaccine is generally offered each winter, although data demonstrating its efficacy in this population are lacking. Passive immunisation of symptomatic children is recommended if they are in contact with varicella zoster virus (VZV) and are either VZV naive or have no detectable specific antibodies to VZV. Varicella zoster immunoglobulin (VZIG) ideally should be given within 72 hours of contact. VZIG may prolong the incubation period to 28 days, so clinicians need to consider isolating these patients at clinic visits. Similarly normal human immunoglobulin should be given for susceptible symptomatic children in contact with measles. If children are stable on HAART with CD4 counts above 15%, passive immunisation is unnecessary. Regular intravenous immunoglobulin infusions (400 mg/kg every 28 days) should be reserved for children with recurrent bacterial infections despite good compliance with cotrimoxazole prophylaxis, or those with proven hypogammaglobulinaemia. Higher doses may be useful in the management of thrombocytopenia (0.5–1.0 g/dose every day, for three to five days). HIV-infected children who are household or day care contacts of individuals with open pulmonary tuberculosis should be carefully assessed, bearing in mind skin testing is frequently unhelpful because of anergy. If there is no evidence of infection, prophylactic isoniazid for six months, or isoniazid plus rifampicin for three months, is recommended. There is little enthusiasm for prophylaxis against Mycobacterium avium intracellulare in children because of adverse reactions and the potential for resistance and breakthrough on single agents such as rifabutin. The most appropriate prophylaxis for all OI is to optimise antiretroviral therapy to restore and preserve immune function. 80 Table 12.6 Suggested doses of co-trimoxazole for prophylaxis for Pneumocystis carinii pneumonia, to be given once daily on three days per week (usually Monday, Wednesday and Friday). Dose is based on 900 mg/m 2 dose

Surface area (m 2 ) 0.25–0.39 0.40–0.49 0.50–0.75 0.76–1.0 > 1.0 Dose of co-trimoxazole (mg) 240 360 480 720 960 (adult dose)



1.0



Proportion surviving



0.8



0.6 Other 1993–97 0.4 PCP/CMV 1993–97 Other anything



toxic?

infection chemotherapy radiation



GIT?

gastric irritation gastric stasis obstruction (mass/ constipation/functional)



CNS?

cerebral irritation? menigeal irritation RICP



metabolic?

renal hepatic Ca etc.



Specific and symptomatic treatment(s)

First line (Box A)

regularly breakthrough



Review 24–48h review cause unresolved Parenteral optimum dose resolved maintenance



Second line (Box B)

add optimise



review cause



unresolved



Refer to Specialist Palliative Care

Box A First-line antiemetics

Prokinetic (gastric stasis, functional obstruction) Metoclopramide 10 mg stat., then 10 mg t.d.s. or 30–60 mg/24h via subcut. infusion (n.b. inactivated by muscarinic drugs) Vomiting Centre (RICP, motion, mechanical obstruction) Cyclizine 50 mg p.o./s.c./i.v. stat then 50 mg p.o. t.d.s. or 150 mg/24h via subcut. infusion Hyoscine hydrobromide as patch 500 mg/72h 5HT 3 Antagonists (metabolic, drugs, radiation, gut distension) Granisetron 1–3 mg p.o./i.v. stat and b.d. or 9 mg/24 h via subcut. infusion

Figure 14.7 Guidelines for pain evaluation



Box B Second-line antiemetics

Broad spectrum Methotrimeprazine 6.25 mg stat 12.5–25 mg/24h via infusion Dexamethasone 4–8 mg daily as one dose mane Prokinetic: Cisapride 20 mg p.o. stat and b.d. Antisecretory drugs: Hyoscine butylbromide 20 mg s.c. stat and 60–120 mg/24h Octreotide 100 mg stat and t.d.s. or 300–600 mg/24h via infusion Cannabinoids: Nabilone 1–2 mg b.d.



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ABC of AIDS

Prescribe the most appropriate first-line antiemetic for the likely cause according to the figure. Prescribe both regularly and as required. If the patient is vomiting, or has been nauseous for some time administer parenterally, preferably by continuous subcutaneous or intravenous infusion preceded by a stat dose. Optimise the dose daily taking into account breakthrough doses and reported level of nausea and vomiting. If there is no improvement, rather than changing the drug, optimise the dose, and re-evaluate the cause. It may influence your drug choice. After 48 hours, substitute or add an appropriate second-line, broader spectrum antiemetic. A significant minority of patients need more than one antiemetic. Consider non-drug treatments, including acupressure bands, control malodour, and ensure patient avoids foods that may precipitate nausea. If control remains poor, then refer. Only consider converting to equivalent oral regimen after 72 hours of good control and continue antiemetics indefinitely unless the cause is self limiting.



Clinical

? disease profile ? treatments ? symptoms



Social

? practicalities ? finances ? safety



Emotional

? mental health ? success in coping ? relationships



Cultural

? health belifs ? prohibitions ? religious need



Existential

? beliefs ? meaning ? guilt and regrets ? hope ? fear and despair



Other common symptoms Other common symptoms are cognitive impairment, weight loss, malaise, weakness, pruritis, cough, diarrhoea, etc. Their differential diagnosis and appropriate investigations and management are covered more widely in the ABC of Palliative Care.



Quality of life

? aspirations ? priorities ? successess ? failures



Suffering

? physical distress ? crises of meaning ? unresolved relationships ? unfinished business



Figure 14.8 Aspects of palliative care: some elements necessary to holistic practice in chronic or progressive disease



Death and dying

When treatment is futile, persevering with treatment and investigation can be obstructive in allowing a patient a dignified and meaningful death. The patient should be at the centre of the decision-making process as much as is possible. It is at this time that the multiprofessional team is so important.



Facilitating choice If you have been managing your patients properly and involving them in decision-making, the groundwork for managing the last weeks or months should have been done, you will have a good enough relationship to be honest and open and to finish these last preparations. If you have not faced these with your patient in some form, even by flagging that “a time will come…” whilst not failing them as a technician, you will have failed as a doctor. This is the time to check regularly about a patient’s wishes. Proper links and services from primary care and social services are essential and friends, family and professionals should be as much “in the know” as possible.



Box 14.13 Preparing for death

• Do they want active treatment if they deteriorate? If so, what level of resuscitation do they want? Is there a time or circumstances in which they wish treatment to be withdrawn or withheld? Will they feel more in control if these are written formally? A ‘Living Will’ or Advance Directive can be of great help to some patients by ensuring that their wishes are known if they become incapable. (See the BMA guidelines “Advance Statements: a guidance to practitioners”.) Have they said their goodbyes, sorrys and thank yous? Are there remaining personal matters to address: a will, funeral preparations, etc? Do they want to be at home? If so, is it suitable?



•



Two additional symptoms Movement-related pain This is a common problem in dying patients with HIV and is best managed with NSAIDs. If the patient cannot swallow, then rectal indometacin is very effective.



• • •



Pulmonary secretions Retained secretions in patients too weak to clear them can be controlled with hyoscine 0.6–1.2 mg s.c. over 24 h or glycopyrronium 0.6–1.2 mg s.c. over 24 hours. If they fail to clear, use furosemide (frusemide). Reassure family that noisy breathing of itself is not distressing to the patient.



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Palliative care and pain control in HIV and AIDS

As death approaches In the last days of life, pragmatism and sensitivity are essential. Patients have no appetite, are weak and somnolent or unconscious. Altered breathing patterns can last for days. Be calm and reassuring: relieve anxiety for both patient and carers by explanation that these changes are normal and don’t cause physical suffering, which is true. Most importantly continue to visit. The clinical situation can change very quickly. Assess symptoms regularly and change palliative therapeutics as necessary (even several times a day). As swallowing becomes difficult swap to parenteral routes. Most drugs for symptom control can be given continuously via a syringe driver subcutaneously. (Drugs can be mixed, see the charts in Twycross et al. 1998.) Figure 14.5 summarises management in the last few days of life. With the limited communication, problems may manifest themselves as pre-terminal restlessness or distress. Possible physical and psychological/spiritual triggers need to be checked and acted on. In general encourage the family to talk normally to the patient and to say whatever they need to say. Reassure them that the patient can hear and continue to explain all that you do to the patient and chat normally through procedures. This period of life, when the dying process is actively underway, may be short lived or take many days. In most cases we do not know what is taking place. Where beliefs are unknown or unfamiliar it is best presented neutrally as a time of transition; when our place is to care.



Box 14.14 Pre-terminal restlessness

• • • • • • Exclude urinary retention Treat any suspected pain Check that there is not an important visitor that the patient must see or hear Check for an important date or anniversary Exclude any important religious rite Sedate as necessary; midazolam (starting at 10 mg/24 h), levomepromazine (12.5–300 mg/24 h).



Check often interfere little Privacy



Good nursing Dying process



Talk to patient even if unconscious Gather “family”



Restless



Discomfort



Breathing



Cause list and treat Sedate lightly Hallucination midazolam 10 mg/24 h Vomiting



General



Altered patterns



Secretions

hyoscine 0.6–2.8mg/24h



LEAVE diamorphine 10 mg/24 h Movement NSAID furosemide (frusemide) 20 mg stat



levomepromazine cyclizine (methotrimeprazine) 12.5 mg 50–150 mg haloperidol 2.5 mg/24 h



advice



TITRATE TO COMPLETE CONTROL REGARDLESS OF DOSE



Figure 14.9 Pain management in the last few days of life



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ABC of AIDS

It is important to allow those with religious beliefs the opportunity to see their advisors and perform necessary rituals as they wish. This can often lead to conflict if partners and family are of differing opinions. Give time to friends and family to spend talking over what has happened. Obviously you must be aware of the dynamics of the group and you must respect the patient’s confidentiality. Finally, a death affects us and the team involved. Debriefings and supervision work either individually or as a team can be most beneficial.



Further reading

• Fallon M, O’Neill, W, eds. ABC of palliative care. London: BMJ Books, 1999. • British Medical Association Advance Statements About Medical Treatment. London: BMJ Books 1995. • Doyle D, Hanks G, MacDonald N. (eds). The Oxford Textbook of palliative medicine, 2nd edn. Oxford: Oxford University Press, 1998. • George R, Houghton P, Robinson V. Healthy dying. London: Jessica Kingsley, 2001 (in press). • Twycross R, Wilcox A, Thorp S. PCF1, Palliative Care Formulary. Oxford: Radcliffe Medical Press, 1998. • British Medical Association. Withholding and Withdrawing Life-prolonging Medical Treatment, 2nd edn. London: BMJ Books, 2001.



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15



Control of infection policies



IJ Hart, Celia Aitken



Intensive epidemiological studies of HIV infection have shown that it is not transmitted in the community by casual or intimate non-sexual contact. As of December 1999 there have been 96 documented instances of confirmed occupational transmission of HIV. There have been, in addition, 171 cases of HIV infection, possibly resulting from occupational transmission in exposed individuals with no other known risk of infection. The rate of transmission after a single percutaneous exposure to HIV positive material is 0.32% (21 confirmed infections after 6498 exposures in 25 studies). The risk of infection after exposure of mucous membranes and/or conjunctivae to infected material is 0.03% (one confirmed infection after 2885 exposures in 21 studies). It is important to design infection control policies which, while protecting staff against the risk of fection, do not compromise medical and dental care. HIV is one of several blood-borne viruses; carriers of these viruses may be perfectly well and individuals may be unaware that they are infected. Some, including the hepatitis viruses B and C, are potentially more infectious than HIV. Thus, healthcare workers and society in general need to adjust to the concept that direct contact with the blood of others may present a potential, albeit low, risk of infection. In the UK the Department of Health and many other bodies have issued guidelines to educate and protect healthcare and community workers. Routine HIV screening of antenatal patients is now recommended, and testing of all those at risk is encouraged. Awareness of the risks, education, careful attention to work practices, provision of protective equipment and immunisation against hepatitis B, where appropriate, are measures which will reduce to a minimum the risk of infection with all blood-borne viruses.



Box 15.1 Selected guidelines

• United Kingdom Health Departments. Guidance for clinical health care workers: protection against infection with blood borne viruses. Recommendations of the Expert Advisory Group on AIDS. London: HMSO, March 1998 A code of practice for sterilisation of instruments and control of cross infection. London: British Medical Association, June 1989 The safe disposal of clinical waste. London: HMSO, 1992 United Kingdom Health Departments. AIDS/HIV infected health care workers. Guidance on the management of infected health care workers and patient notification. Recommendations of the Expert Advisory Group on AIDS. London: DOH, March 1998 Advisory Committee on Dangerous Pathogens. Protection against blood borne infections in the workplace: HIV and hepatitis. London, HMSO, 1995 Royal College of Pathologists. HIV and the practice of pathology. London: Marks & Spencer Publication Unit of the Royal College of Pathologists, July 1995 United Kingdom Health Departments. HIV post exposure prophylaxis: Guidance for the UK Chief Medical Officers Expert Advisory Group on AIDS, July 2000. General Medical Council. Serious communicable diseases. London: HMSO, 1997



• • •



•



•



•



•



Hospital care

HIV positivity per se is not an indication for isolating a patient in hospital. It may be necessary to consider source isolation, however, if there is evidence of active infection with other agents, such as Mycobacterium tuberculosis, varicella-zoster virus, or if there is a likelihood of extensive exposure to body fluids from, for example, haemorrhage or severe diarrhoea. Medical practices should be of a sufficiently high standard to eliminate any risk of patient-to-patient spread of HIV in hospital. This is achieved, as part of general infection control procedures, by using disposables, and by paying careful attention to decontamination and sterilisation. Attempts to recycle disposables or to bypass accepted disinfection procedures may lead to nosocomial infection. Staff should adopt sensible precautions if contamination with blood or other body fluids is likely. This applies particularly for the management of known virus carriers but should also be the routine for any patient. The concept of “universal precautions” for all patients is being introduced increasingly into healthcare. In most cases precautions entail no more than wearing disposable gloves and an apron, but in certain circumstances, such as bronchoscopy, protective spectacles and a mask may be necessary to protect the eyes and mouth. Most aspects of patient care and examination do not



Figure 15.1 Bronchoscopy in a patient infected with HIV



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ABC of AIDS

expose the staff to body fluids, and protective clothing is not required. Many staff sustain inoculation injuries while manipulating needles and sharp instruments. Education and careful attention to technique will reduce the risks to a minimum. No attempt should be made to resheathe needles unless a safe resheathing device is available, and needles should be placed immediately into safe sharps disposal containers, which should not be overfilled. Although there is little epidemiological evidence of increased risk, many hospitals assume that special care should be taken during surgery on known or suspected HIV carriers. This usually means adopting pre-existing policies for hepatitis B carriers and may include the introduction of double-gloving and additional protective clothing. Preventing unnecessary exposure to body fluids and trying to reduce the incidence of penetrating injuries to a minimum are the best defence against infections, which may be present, but unsuspected, in any patient. Reports of transmission of HIV from a dentist to his patients have raised public concerns about the risks of acquiring HIV and other blood-borne viruses from healthcare workers. Guidelines produced by the UK Health Departments identify work practices known as “exposure-prone invasive procedures” as aspects of medical care that present a potential risk of transfer of a blood-borne virus from healthcare workers to patients. Exposure-prone procedures are those where there is a risk that injury to the worker may result in the exposure of the patient’s open tissue to the blood of the worker. These procedures include those where the worker’s gloved hands may be in contact with sharp instruments, needle tips or sharp tissues (spicules of bone or teeth) inside a patient’s open body cavity, wound or confined anatomical space where the hands or fingertips may not be completely visible at all times. Healthcare workers who are HIV positive or HbeAg positive carriers of hepatitis B are excluded from exposure prone procedures. HbeAb positive carriers are excluded if there is >10 3 copies/ml of HBV DNA in their blood. There are many reports of hepatitis B transmission from staff to patients but only one report of HIV transmission from a surgeon to one of his patients during orthopaedic surgery. The risk of HCV transmission from staff to patient is still not known but may be higher than previously thought. Clearly, the risks to the patient from HIV in health care workers are extremely low but the frequency of inoculation injury to the surgeon during the course of major surgery highlights the need for continued surveillance.



Figure 15.2 A vacuum collection system of the type shown reduces the risk of spillage when large volumes of blood are required



Sharps disposal

Clinical laboratory staff are at risk from certain pathogens which may be present in specimens. The Advisory Committee on Dangerous Pathogens originally produced specific guidelines for work on samples from HIV positive patients. These have now been reissued to encompass potential risks from all bloodborne viruses. The most important aspects of safety in the laboratory are education, training, and prevention of inoculation and skin contact with body fluids. It is important to review all laboratory procedures to reduce the use of needles and the danger of exposure to glass fragments. This may necessitate increased investment in automatic pipetting systems to replace the need for glass pipettes. The absence of evidence of airborne transmission means that HIV positive samples may be handled on the open bench providing the work is conducted in optimal facilities and the operator is free from distraction and 96



Figure 15.3 Safe sharps disposal



Control of infection policies

disturbance. The current practice of alerting laboratory staff to samples from known or suspected HIV positive patients by the use of biohazard stickers may be defended on the basis that it reduces risks. It must, however, be emphasised constantly that in the present epidemic no unfixed specimens can be considered free from infection. Box 15.2 Community aspects of decontamination

• • Cutlery, crockery, clothing decontaminated by normal washing Decontaminate blood spillages with bleach (hypochlorite)



Community aspects

HIV carriers m the community present no risk to others from normal day-to-day contact. The combined effects of dilution, temperature and detergent action ensure that standard washing procedures will satisfactorily decontaminate cutlery, crockery and clothing. All blood spillages should be decontaminated with hypochlorite (bleach) and carefully cleaned up. The absence of evidence that saliva can transmit HIV means that nobody should withhold mouth-to-mouth resuscitation from someone who has suffered a respiratory arrest. Members of the rescue services who frequently carry out resuscitation, often in cases in which facial injury exposes them to blood as well as saliva, are provided with masks and other devices. Anyone attempting to use a resuscitation device must be adequately trained as, in the wrong hands, it may prejudice the life of the casualty and in some cases increase the potential risks to the operator by causing bleeding.



Figure 15.4 Secure bagging for specimen and request sent to laboratory



Disinfection

An important method of reducing the potential infectivity of viruses is dilution. Thus procedures such as thorough cleaning and handwashing are central to any infection control policy and must never be neglected. HIV has been described as a fragile virus, and this is true to an extent. Although it is effectively inactivated by many different agents, survival of virus may be prolonged at ambient temperatures, and infectious virus may still be present in dried blood after a week. This means that any surfaces and fomites that have been in contact with clinical material must be decontaminated. The trend towards the use of disposables reduces the need for decontamination in many areas. Thorough cleaning followed by heat sterilisation should be adopted, if at all possible, for any reusable equipment. Although HIV is inactivated by boiling, autoclaving has become the norm in clinical practice. With increasing numbers of HIV carriers in the community it is important for their protection to ensure that instruments are rendered free of all organisms, including bacterial and fungal spores. Organisms that may present no risk to people with normal immunity may lead to opportunistic infections if they are immunocompromised by HIV infection or other agents such as chemotherapeutic drugs. Liquid disinfectants must always be considered a poor alternative to heat sterilisation. Difficulties exist controlling their potency, most are caustic, and most are rapidly inactivated by organic matter. For hospital or community use, if it is necessary to use a liquid disinfectant, it is sensible to choose one which is known to inactivate hepatitis B and other pathogens such as Mycobacterium tuberculosis, as well as HIV. All waste that is contaminated with blood must be considered potentially infective and treated as “clinical waste” in accordance with the Health Services Advisory Committee’s document “The safe disposal of clinical waste”. Sharps containers must meet Department of Health specifications and must be incinerated before disposal.



Box 15.3 Disinfection

• • • • Autoclave or use disposables if possible Hypochlorite (1000 ppm available chlorine) for general decontamination Hypochlorite (10 000 ppm available chlorine) if organic matter, including blood, present 2% Glutaraldehyde (freshly activated) NB: Beware of dangerous fumes



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ABC of AIDS



First aid and inoculation injuries

In the event of exposure to blood, simple first-aid measures should be applied immediately. Any blood or other body fluids on the skin should be washed away with soap and water. Splashes into the mouth or eye should be diluted by washing, and sterile eyewash bottles should be provided in any areas where this is likely to occur. A skin puncture should be encouraged to bleed in an attempt to express any material deposited in the wound. The wound should then be washed thoroughly. Any injury to a member of staff should be reported immediately to the person in charge and then to the occupational health physician or other medical adviser. In hospital this allows for the opportunity to investigate the state of health of the person inoculated and, if necessary, to take protective measures such as hepatitis B prophylaxis or antibiotic cover, or testing the source patient or the use of antiretroviral drugs. At present the recommended drugs for postexposure prophylaxis are zidovudine, lamivudine and indinavir. They should be taken for four weeks. An acceptable recommended alternative regimen is the use of nelfinavir instead of idinavir. However, allowances for pregnancy, drug interactions and potential antiviral resistance in the source may result in some modification to the final regimen. In these circumstances expert advice should be sought. The medical adviser should discuss whether blood samples should be taken for future reference of HIV testing and whether a programme of follow-up consultations should be started. The medical adviser will need to obtain information about the source patient concerning possible indicators of HIV infection, including risk factors and results of previous HIV tests, medical history suggestive of HIV infection, and details of past and current antiretroviral therapy in patients known to be HIV infected. The source patient should be asked to consent to testing for HIV infection. This will entail pre-test discussion and obtaining fully informed consent. If the patient is unconscious when the injury occurs consent should be sought once the



Box 15.4 First aid

• • Body fluids on skin, in eyes, or in mouth wash away immediately Penetrating wounds encourage bleeding wash with soap and water report to the supervisor and medical officer



patient has regained full consciousness. If the patient refuses testing, is unable to give consent because of mental illness or disability, or does not regain full consciousness within 48 hours, testing should be considered in exceptional circumstances only, such as where there is good reason to think that the patient may be HIV infected. In this case testing an existing blood sample for HIV infection may be done but only after consultation with an experienced colleague. The decision to test may be challenged in courts so be prepared to justify the decision. Only the source patient and those exposed to the infection may be told the result of the test and the result can only be entered into the patient’s personal medical record with the patient’s consent. If the patient dies HIV testing can be done if there is good reason to think the source patient may be infected. It is usual to seek the agreement of a relative before testing. Those concerned with counselling people who have sustained inoculation injuries should have enough knowledge to provide current information about the risks of occupational exposure and should be able to advise on changes in lifestyle such as the adoption of safer sex practices. In summary, the risk of transmission of HIV within hospitals and to carers in the community is low. Education of staff, good infection control procedures and safe working practices can help to minimise this risk. Due attention to these measures at all times will ensure the protection of patients and staff.



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16



Strategies for prevention



John Imrie, Anne M Johnson



Introduction

Limiting the spread of HIV relies on health promotion activities to encourage and help sustain behavioural changes that reduce the risk of acquiring or transmitting the virus. Despite advances, the prospect of a widely available effective vaccine remains some distance off and behavioural interventions are likely to remain the backbone of HIV prevention for the foreseeable future. Appropriate prevention strategies are required in both developed and developing country settings and must be specific to the cultural, epidemiological and socioeconomic environment of each country. This chapter focuses on HIV prevention strategies in the UK although some of the principles outlined are generalisable to other countries (chapter 10). This chapter deals with sexual and parenteral transmission of HIV. The prevention of perinatal transmission is addressed in chapter 12.



General health education

Government information campaigns and media attention in the 1980s raised the general public awareness of HIV/AIDS. Knowledge of transmission routes and risk reduction strategies (for example, condom use and reducing partner numbers) remains high, although public campaigns for HIV risk-reduction no longer have the same profile in the UK. Recent increases in sexually transmitted infections (STI) (for example, chlamydia and gonorrhoea) and high teenage pregnancy rates indicate that safer sexual practises are not consistent among young people. Age at first intercourse continues to decline and while there is some evidence of increased condom use in many countries, there has been little change in the numbers of people reporting multiple sexual partners. Those at greatest risk of poor sexual health outcomes are men who have sex with men, the under 25s, injecting drug users and their partners, inner city populations and some ethnic minority populations Epidemiological data show an increasing trend in the number of heterosexually acquired HIV infections diagnosed in many developed countries. In the UK in 1999, for the first time the number of newly diagnosed HIV infections acquired hetrosexually exceeded those acquired through sex between men. However the majority of heterosexually acquired infections in the UK remains among those with sexual partners in Africa (chapter 1). These trends indicate the continued importance of general health education strategies for HIV prevention and sexual health promotion. Prevention messages can be delivered in many different settings, ranging from mass media, school sex education, community and youth organisations, through individual interventions in primary care, contraception services and specialist STD services. All health professionals can provide practical information and personally tailored messages to individuals. Given the particular risk among young people, education for HIV prevention needs to take place in the broader context of sexual health education in schools, before young people become sexually active, as part of Personal Health and Social Education (PHSE). To remain effective over time, however, school-based sexual health and general HIV education strategies need to be



Figure 16.1 Dutch scratch card shows prevention messages can be delivered in different settings using a range of age appropriate techniques reproduced with permission from the Dutch Foundation for STD Control



Figures 16.2a and b Sex education content and delivery should be gender sensitive and take account of the different needs of boys and girls reproduced with permission from the Family Planning Association



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ABC of AIDS

sustained, politically supported by central and local government, financially secure, and routinely assessed and revised to meet the changing needs of new generations of sexually active young people. Current approaches to sex education in schools include both teacher-led and peer-led approaches. Generally outcomes of sex education have been poorly evaluated and the most effective methods of delivering sex education for achieving improvements in sexual health outcomes are uncertain. However, observational studies have indicated some key components of effective sex education programmes. Several randomised trials are currently under way examining a range of approaches, and they will hopefully provide some more definitive answers. Box 16.1 Approaches to sex education most likely to improve sexual health outcomes in young people:

1. Begin early (i.e. sex education should start with pre-teens) 2. Cover issues in an incremental and age-appropriate fashion 3. Address knowledge and attitudes, and provide practical skills (for example, using condoms) 4. Provide information, improve knowledge and build confidence to access sexual health and contraceptive services 5. Employ participative approaches (for example, role play) 6. Ensure content and delivery are gender sensitive, taking into account the different needs of boys and girls 7. Ensure understanding of different sexual choices (for example, delaying first intercourse, resisting pressure for sex) and different sexualities 8. Deliver interventions in a range of settings across the community (for example, involve parents and youth services)



Preventing sexual transmission

The epidemiology of HIV within the UK indicates that the greatest risk of infection is still associated with particular behaviours or demographic characteristics. Identified behaviours with the highest risk of HIV infection are: sex between men, injecting drug use; sex with injecting drug users, and sexual contact in parts of Africa and other parts of the world, where heterosexual transmission predominates. In other parts of the world commercial sex workers are at greatly increased risk of HIV. In the UK, other than among sex workers who are also injecting drug users (IDUs), high rates of condom use with commercial partners have maintained low HIV prevalence among prostitutes. While there has been massive expenditure on HIV prevention over the last decade, until recently there has been a dearth of high-quality evaluation and little evidence from randomised trials to demonstrate effectiveness of different interventions. However, there is now a growing evidence base to support targeted HIV prevention interventions, tailored to the cultural context and needs of particular groups. A small number of randomised trials have shown the interventions to be effective in reducing the frequency of specific risk practices (for example, unprotected penetrative vaginal or anal intercourse) and, in a few cases, the incidence of new STI. In general, these interventions have aimed to provide basic HIV/AIDS education (including instruction on correct and appropriate condom use), enhance motivation for behavioural change, and teach risk reduction and safer sex negotiation skills (including the ability to resist pressure for sex) and have been delivered in community, small group and individual settings. However, effective interventions in a research setting may not yield the same results in “real life”. Careful consideration of local HIV epidemiology with a critical view of the generalisability of the intervention, will help to determine whether a specific intervention is appropriate and prevent spending limited resources on a programme that shows little benefit, or worse still, a negative effect. The literature contains examples of both. No single intervention strategy is likely to be sufficient to address all of a group’s prevention needs. There is no evidence that “single-shot” prevention interventions have enduring effectiveness at a population level. Interventions need to be sustained, with careful monitoring to indicate when changes are necessary, and must adapt, particularly, to the evolving epidemiological, social and cultural changes in successive new generations. Little has changed with respect to the core content of prevention messages: it requires sexual contact involving the exchange of body fluids or blood-to-blood contact for transmission to occur. Those who know they are HIV negative and in a mutually monogamous relationship, are not at risk of 100



Box 16.2 Practises that reduce the risk for acquisition or transmission of HIV

• • Using condoms for all penetrative sexual intercourse Using adequate quantities of water-based lubricant for both vaginal and anal intercourse. (Oil-based products will cause latex condoms to perish. Lubricants containing spermicides (for example, Nonoxyl 9) may cause irritation and have not been demonstrated to be effective in reducing HIV transmission in vivo) Reducing numbers of sexual partners Adopting sexual practises that carry a lower risk for HIV transmission (for example, oral sex, mutual masturbation) Avoiding recreational drug use during sexual activity, or when sex is likely to happen Ensure timely screening and treatment for suspected STI For young people, delaying the age at which first sexual intercourse takes place



• • • • •



Strategies for prevention

infection through sex. To limit sexual risk of infection, the most effective strategies are to reduce numbers of sexual partners, know about partners’ previous sexual and drug-use history and adopt safer sex practices (for example, oral sex, mutual masturbation and use condoms). Although condoms do not provide total protection, correct and consistent use will substantially reduce the sexual risk of HIV, STI and pregnancy. The challenge that remains is how to deliver innovative HIV prevention messages through a range of different community, and individual focused interventions to reduce HIV transmission. The following sections examine some effective strategies in relation to specific populations at high risk.



Gay, bisexual and other men who have sex with men

In most industrialised countries, homosexual and bisexual men have been disproportionately affected by HIV/AIDS. Unprotected anal sex is the primary mode of transmission and receptive intercourse carries the greatest risk. The success of early safer sex promotion campaigns primarily led by gay organisations has been highlighted as one of the greatest early successes in HIV prevention with evidence of falling STI rates, stabilisation in HIV prevalence and rapid uptake of safer sex practices. Over time these changes have proved difficult to sustain. Although condom use has become a social norm within the gay community, in recent years increasing proportions of homosexual men are engaging in unprotected anal sex. This particularly involves sex between men who are known to be HIV positive, partners whose HIV status is unknown to each other and younger men (< 25 years) who are likely to have become sexually active in the era of HIV/AIDS, and were not exposed to the intensive campaigns of the mid 1980s. Factors which may contribute to increasing risk behaviour include: “boredom” with prevention messages; failures to target appropriate messages to a new generation of gay men; and perceived decreased threat of HIV in the era of highly active antiretroviral therapy (HAART). The content of the successful interventions targeting gay men varies, but have often included motivational training, audiovisual presentations (for example, eroticising safer sex), brief safer sex negotiation skills training, stress reduction training and intensive group counselling. Interventions such as these are likely to attract individuals with particular concerns about their sexual risk behaviours and greater motivation to address them, so such interventions alone are not likely to meet all of the prevention needs of men who have sex with men. These interventions are particularly relevant to men using genitourinary medicine (GUM) clinics and HIV testing services. Knowing that face-to-face interventions will never be able to reach all of the people at risk, community level strategies offer the potential of reaching those who do not attend services. Broader strategies focused at the community level have been shown to be effective in reaching higher risk and vulnerable men who often do not participate in small group interventions. Prevention programmes involving outreach workers and peereducators can be used to target men using community venues (for example, bars, clubs, saunas), public sex environments (for example, cruising grounds, public toilets) and other places where homosexual men meet to have sex. These strategies often follow the principals of empowerment or community-building models of health promotion, with the intervention being developed either by gay communities themselves, or in collaboration with public health or sexual health providers. The



Figure 16.3 Face-to-face interventions may be particularly relevant for persons attending health care and other services reproduced with permission from the Terrence Higgins Trust



16.4 HIV testing has important primary prevention value with some carefully defined groups reproduced with permission from the New Zealand AIDS Foundation



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ABC of AIDS

content of successful community-focused interventions varies, but among the most important components are peer and opinion-leader delivery of risk reduction messages, communitybuilding activities and peer-outreach providing safer sex materials (i.e. condoms and lubricant). One of the very few rigorously evaluated and effective interventions that specifically targeted young gay men (for example, aged 18–29) was developed using these approaches. Box 16.3 Effective HIV prevention strategies targeting injecting drug users

• • • Making easily available sterile needles and syringes User-friendly, low-threshold drug treatment programmes, including oral methadone maintenance Sustained education through outreach programmes and peer education providing information, skills (for example, safer injecting ), health services and social support Providing access to counselling and HIV testing Facilitating access to health care, support and STD services for IDUs with HIV infection Special programmes for high-risk subgroups (for example, sex workers, prison inmates, youths in detention)



Injecting drug users

HIV transmission between injecting drug users (IDUs) occurs primarily through sharing of HIV-contaminated syringes, needles and injecting equipment. IDUs and their partners are also at risk through sexual transmission. Since many, particularly female, IDUs support their drug habit through commercial sex they may be at risk of sexual transmission both to and from their commercial and non-paying partners. The epidemiology of HIV infection in IDUs and the social and cultural context of drug use vary substantially between geographical areas. Identifying promising interventions most likely to succeed within a particular setting is reliant upon understanding the local epidemiology and drug-use culture. Preventing HIV transmission in injecting drug users relies primarily on reducing the frequency of sharing needles, syringes and other paraphernalia used for injecting (“works”), and on ensuring that the risk of sexual transmission for paying and non-paying partners is minimised through safer sex practices. Effective strategies that reduce the risk of HIV transmission through injecting will have other benefits in reducing the incidence of other viral infections (for example, hepatitis B and hepatitis C). Social, political and legal controversies have hampered prevention strategies to minimise the potential harm of injecting drug use to both the individual and the community, because of particular concerns that increasing the supply of clean injecting equipment would encourage injecting drug use. Research evidence from largely observational evaluations has shown these concerns to be largely unfounded. Observational studies have demonstrated that needle exchange programmes (i.e. providing sterile needles and syringes in exchange for used ones) are the most effective base for prevention strategies with drug users. Needle exchange has been successfully delivered within health and social services, through outreach workers, and dispensing machines, and has been demonstrated to be associated with reduced HIV prevalence without increasing levels of drug use. Improved access to bleach cleaning kits (for shared needles and syringes) and training in effective cleaning procedures may reduce HIV transmission through needle sharing. However, the quality of available products and the complex skills required make this a poor substitute to access to clean needles, but better than no intervention at all. Evidence supports outreach and peer-educators as the most effective way to reach drug users in the community. Former injectors and current injectors have been employed successfully in both roles. Other interventions, specifically low-threshold easy-access drug treatment programmes and oral methadone maintenance, have been shown to reduce overall levels of drug injecting. These interventions bring drug users into regular contact with service providers (whether outreach or service based), where opportunities to deliver other information, education and counselling interventions exist. In particular, treatment and methadone maintenance programmes can offer adjunct social, educational and rehabilitation interventions to break the cycle of drug use and increase the possibility of an individual’s integration into routine employment and 102



• • •



Figures 16.5a and b An example of good practice in provision of effective accurate information for injecting drug users, reproduced from “A Guide to Safer Injecting”. with permission from HIT



Strategies for prevention

mainstream culture. A supportive environment including political, financial and legal support for the programmes at both central government and the local level is essential for the longterm success of comprehensive programmes. In parts of the world such as the USA where IDUs have suffered a particularly severe HIV epidemic, sexual transmission to the partners of IDUs is a major source of increasing heterosexual transmission. Programmes to prevent sexual transmission among IDUs have received much less attention than those for harm minimisation from injecting and there has been little demonstrable success in changing the sexual behaviour of IDUs. Approaches to changing behaviour in this population clearly need to incorporate those shown to be appropriate to all heterosexual populations. In addition, approaches that have shown some promise specifically among drug users include skills training in correct condom use, voluntary HIV testing and counselling, and sexual negotiation skills. Such programmes need to target in-treatment drug users, sex workers and female sexual partners of male drug users. Box 16.4 Guidance for enhancing sexual health promotion and HIV prevention in minority ethnic communities

• Facilitating access to appropriate confidential adolescent and adult sexual health and HIV prevention services, including specialist services outside routine clinical settings inline with the expressed needs of the community Developing materials using appropriate language and images including materials appropriate for non-native Englishspeakers Early and continued sex education in schools to supplement and support provision in the home Assisting parents from cultures where sex in general is rarely discussed to discuss sex education Providing focused interventions for young boys in either school or community settings Prohibitive messages may be supported by some particularly older generations Exploiting and explaining the wider benefits of safer sex in relation to contraception and avoidance of other infections may increase the overall acceptability of messages with all audiences Focused work exploring assumptions made about “safe” partners and concurrent relationships in cultures where they are common Use of appropriate and community-specific delivery points, for example, settings appropriate to the specific culture Awareness of different migration, refugee and acculturation experiences between communities and between generations Promoting HIV testing within high-risk ethnic communities is likely to be extremely sensitive and should be treated with careful consideration and caution based on a clear understanding of the individual and community issues



•



• • • • •



African and other ethnic minority communities

African and ethnic minority communities have become an important focus for targeting HIV prevention interventions, however evidence for effective interventions with this group is limited. The few interventions that have been rigorously evaluated have been developed in careful collaboration with the affected communities. They have considered carefully the cultural and social factors influencing sexual attitudes of the communities and treated HIV prevention within the context of wider sexual health, contraception and pregnancy. Within the UK context recent research into the sexual attitudes and lifestyles of diverse ethnic communities has provided guidance for the development of linguistically and culturally appropriate strategies. African communities in the UK are particularly severely affected by HIV. Many within these communities also face the additional challenges of relatively recent migration including problems of language, culture and isolation often along with possible economic and/or legal difficulties associated with refugee status. All these difficulties may in turn limit access to local service for treatment and HIV prevention.



•



• • •



Strategies for people with HIV infection

Until recently targeting prevention interventions to HIV positive individuals has been largely neglected. Affected communities have been understandably concerned about stigmatisation and discrimination, while those responsible for prevention have felt poorly equipped to tackle many of the key issues. As stigma and exceptionalism associated with HIV diminishes, opportunities emerge to build HIV prevention strategies where people living with HIV are partners in development and delivery of the interventions. The advent of highly active antiretroviral therapy (HAART) has led to improved survival and thus to an increasing number of people living with HIV in the population. This brings with it particular public health challenges for individuals and society. Clinicians and policy makers need to be aware that with widespread use of HAART comes responsibility for ensuring that the risk of transmission, and particularly the transmission of resistant or virulent strains, is minimised and that public health is protected. For those living with HIV, HAART may lead to improved quality of life and sexual relationships and increased longevity, but also raises the challenge of maintaining life-long safer sex



Figure 16.6 Key materials should be available using appropriate language and images for minority groups and for non-native English speakers



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ABC of AIDS

practices to avoid infecting others. Collectively, increased survival leads to a larger pool of infected people in the community who may pass on infection and there is already evidence that new HIV infections may once again be increasing in parts of the USA. While there are theoretical reasons to believe that HAART may decrease infectivity by decreasing viral load, at the population level, such gains may be counterbalanced by increased unsafe sexual behaviour, increased incidence of STIs, and the emergence of drugresistant strains amongst those failing therapy, which in turn may lead to new infections resistant to currently available therapies. Prevention trials specifically with those living with HIV are scarce. However, recent research and community consultation has provided indications of acceptable primary prevention approaches. Acceptable primary prevention strategies with HIV positive people include providing counselling and support in both one-to-one and small group contexts, providing specialist sexual health and STI screening services for HIV positive people, and offering social, emotional and sexual counselling support within HIV outpatient treatment services. As with other groups, interventions are more likely to achieve success if they occur in genuinely productive partnerships with leadership from the affected communities to overcome wider social prejudice and stigmatisation. Contact addresses and numbers for further information

• • • • • • • • • National AIDS Helpline: 0800 567123 Health Development Agency, Trevelyan House, 30 Great Peter Street, London SW1P 2HW. Tel: 020 7222 5300 National Aids Trust, New City Cloisters, 196 Old Street, London EC1V 9FR. Tel: 020 7814 6767 The Terrence Higgins Trust, 52/54 Grays Inn Road, London WC1X 8JU. Helpline: 020 7242 1010 (noon to 10 pm every day) The Haemophilia Society, Chesterfield House, 385 Euston Road, London NW1 3AU. Tel: 020 7380 6000. DrugScope, Water Bridge House, 32–36 Loman St, London SE1 0EE. Tel: 020 7928 1211 Cardiff AIDS Helpline (10 am to 8 pm Mon-Fri). Tel: 01222 223443 Northern Ireland AIDS Line, Belfast (7 pm to 10 pm) Mon–Fri. Tel: 01232 326117 The Sandyford Initiative, 6 Sandyford Place, Sauchiehall St, Glasgow G3 7NP (8.30 am to 4.30 pm Mon, Wed, Fri; 8:30 to 7 pm Tue and Thur.) Tel: 0141 211 8601 London Lesbian and Gay Switchboard. Tel: 020 7837 7324 Gay Men’s Health, 10A Union Street, Edinburgh EH1 3LU. Tel: 0131 558 9444



• •



Voluntary counselling and HIV testing

Diagnosis of infected individuals has an important role in secondary prevention, because it allows infected individuals to benefit from treatment to reduce the chance of progression to severe immunodeficiency. Identifying those who are HIV positive in order to work with them to prevent onward virus transmission is also fundamental to primary HIV prevention. Routine HIV antibody testing of pregnant women is now recommended throughout the UK. Positive women can then benefit from antiretroviral therapy to prevent perinatal transmission of HIV and advice to avoid transmission through breast feeding. Detailed recommendations on the management of HIV positive pregnant women is dealt with in chapter 12. HIV counselling and testing is widely available in many clinical settings in the UK, particularly in genitourinary medicine (GUM) clinics. Counselling for HIV testing was originally developed in the pre-antiretroviral therapy era and much of the content focused on the nature and interpretation of the test, and the advantages and disadvantages of knowing ones’ status in the context of an untreatable infection. All clients were also advised on risk-reduction strategies to prevent the acquisition or transmission of HIV through sex or injecting drug use. In the era of HAART, GUM clinics are increasingly offering routine testing and counselling as part of their clinical services in order to identify HIV positives. The effectiveness of testing and counselling services in achieving behavioural change for primary prevention is limited and somewhat confusing. Brief client-centred counselling has been shown to be an effective strategy in reducing future STI acquisition in only one large-scale trial, while another study demonstrated its effectiveness in different developing countries using behavioural change endpoints. However, two major reviews of the effectiveness literature have concluded that testing and counselling are only effective as primary prevention strategies for achieving sexual behaviour change within carefully defined groups, including in-treatment drug users, commercial sex workers and post-test counselling and support for those who receive a positive result. Nevertheless, for its secondary prevention benefits and primary prevention value with specific groups, voluntary 104



Figure 16.7 Effective prevention for people with HIV needs to overcome wider social prejudice and stigmatisation, reproduced with permission from the Terrence Higgins Trust



Strategies for prevention

counselling and HIV testing is still an important component of any comprehensive HIV prevention strategy. The testing scenario has much to offer with respect to individually focused prevention. The process of HIV testing offers an opportunity to use a client-centred counselling approach to undertake an individual risk assessment, discuss and develop individually tailored personal prevention strategies and consider the implications of a positive result.



Control of sexually transmitted infections (STIs) and STI screening

There is now substantial evidence from observational, biological and intervention studies to show that STIs (both ulcerative and non-ulcerative) may increase the susceptibility of uninfected individuals to HIV and increase the infectiousness of HIV positive individuals. Control of STls therefore has an important role in the primary prevention of HIV. In the UK, the network of GUM clinics provides open-access services for screening, treatment and partner notification for STIs. STI control is particularly important among populations at high risk of HIV infection. Screening and treatment offer an opportunity to focus behavioural interventions on those who have STIs. Increasingly, GUM clinics are recognising the importance of offering regular STI screening as part of routine HIV treatment services alongside appropriate counselling on risk-reduction strategies. In developing countries, where the burden of untreated STIs is much greater and diagnostic and treatment services more limited, syndromic management approaches have been used. These combine clinical history with knowledge of local pathogens to devise treatment algorithms. Such strategies however appear to be most effective in terms of their specificity and sensitivity in identifying STI cases, where the prevalence of STIs is high.



Blood transfusion and blood products

In,the UK and other developed countries, the risk of HIV transmission through blood transfusion has been minimised by testing all blood samples for HIV antibody and excluding those at increased risk from HIV from donating blood. The current categories for exclusion from blood donation in the UK are shown in Figure 16.8.



Travel to countries with high HIV prevalence

In some countries in Africa, HIV prevalence in the general population exceeds 20% and STI rates are much higher than in the UK. Unprotected sex is therefore associated with a high risk of both HIV and STI infections. All travellers to these countries need clear advice on sexual risk reduction through limiting sexual partnerships and always using condoms. There is no risk of transmission from casual contact. However, in some countries, HIV screening programmes for blood transfusions are not always in place, and there may be shortages of sterile medical equipment for injections and intravenous infusions. Sterile needle packs, first-aid kits (including needles, syringes and suture packs) and minor surgery kits are available for purchase or mail order from the Hospital for Tropical Diseases (London) Travel Clinic (2nd Floor Mortimer Market Centre, off Capper Street, London WC1E 6AU, tel. 020 7388 9600). Basic needle packs and larger made-to-order first aid and surgical packs can be ordered from Nomad Travellers Store and Medical Centre (3–5 Wellington Terrace, Turnpike Lane, London N8 0PX, tel. 020 8889 7014).



Figure 16.8 Government advice to those who should not give blood. Reproduced with permission from the Department of Health Publications



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17



Being HIV antibody positive



Jonathan Grimshaw



Late in, 1984, when I was tested, HIV had only just been identified as the cause of AIDS. There was no formal counselling before or after testing, no organised emotional or social support in the community and certainly no prospect of treatment. The doctor who gave me the positive test result told me, kindly, that I seemed the sort of person who would be able to cope. I agreed. Never having been confronted by anything like this before I was ignorant of what “coping” would involve. Initial reactions I was very frightened. I was convinced I was going to die painfully and soon. I felt very alone. I knew no one else in the same situation. Public fear of AIDS and stigmatisation of “AIDS carriers” were at their height. Confiding in people, even friends, risked hostility and rejection, but I knew equally that friendships would not survive the level of deceit needed to conceal something so devasting. I thought I would never know sexual intimacy or love again. At that time, safer sex was not common behaviour; asking for it could raise the suspicion in a potential partner’s mind that you “had AIDS” and no one, I thought, could possibly want to be intimate with or have a relationship with someone who had the “AIDS virus”. I expected, through illness, to lose my income, my security, my independence, my dignity and my self-esteem. I came to realise how much the things that give a life meaning and purpose – aspirations, dreams, motivation, hope, endurance, fulfilment – depend on the unconscious assumption of a future. Coping with HIV meant firstly coming to terms with the loss of that assumed future and secondly trying to give life some meaning and purpose in its absence. This comes with hindsight. At the time I couldn’t cope at all and spent much of the first few weeks after diagnosis drunk or tranquillised. Peer support, counselling and referral At the end of 1984 the Terrence Higgins Trust established its first support group for people diagnosed with HIV. It gave me and the others there a safe environment in which, for the first time, we could talk openly and honestly about what had happened to us. Most importantly, hearing other people describe feelings and experiences almost identical to one’s own made each of us realise that we were not alone. Learning that the frightening and unfamiliar extremes of fear, anger and grief that each of us had felt were a common and natural reaction to the situation we were in was the first step in our being able to see ourselves again as normal people rather than the “AIDS carrier” pariahs of popular perception. The potential psychological and social impact of a positive HIV antibody test result are now well understood, as is the importance of counselling and referral to agencies that can support people emotionally and practically as they come to terms with the diagnosis and its implications for their lives. For many people, peer support continues to be a key part of that process. Coping with uncertainty It took some time for it to sink in that the positive result wasn’t necessarily a sentence of imminent death, but no one could tell me how long I had to live. In many ways an AIDS diagnosis would have been easier; it would have given me something 106



concrete to deal with. Being HIV antibody positive was a kind of limbo where you knew the axe would fall, but never when. How people cope with this kind of uncertainty probably reflects how they cope with uncertainty in other areas of their lives; some avoid thinking about the future if it threatens contentment in the present, some throw themselves aggressively into trying to shorten the odds in their favour, some fatalistically assume the worst and prepare themselves for it. My way of coping was to throw myself into community work developing services for people with HIV and prevention campaigns and establishing Body Positive. This was the first self-help group in the UK, and perhaps the world, for people with HIV. If I couldn’t fight the HIV inside me, I could at least fight the HIV outside me. I became very driven because, like many people confronted at a relatively young age by their mortality, and not knowing how long I had left, I didn’t want to die insignificantly. I had a lot to achieve with perhaps very little time. One would very occasionally hear someone with HIV say that the diagnosis was the best thing that had ever happened to them. More than any other event or crisis, it forced them to think about what was important and re-arrange their lives accordingly. Certainly, the years after my own diagnosis were lived with an intensity and with a sense of fulfilment in my work that would probably not have been achievable without HIV to concentrate the mind. Retirement In the early 1990s my CD4 count, which had been declining very slowly over time, suddenly seemed to plummet and I developed some minor illnesses. In fact, the CD4 count never fell below the lower limit of what would be considered a normal range, but I convinced myself that the suddenly rapid decline meant that the deterioration to AIDS had begun. I retired from work, cashed in my pension and bought a nice place by the sea in which to pass my remaining few years. I had achieved what I needed – to feel that I had done something useful with my life – and I was completely ready for death. After leaving work, my CD4 count stopped declining and I remained well. In retrospect, the retirement was probably necessary as I was almost certainly approaching “burn-out”, but it felt at the time as though HIV had fooled me into a premature withdrawal from life. During 1997 my viral load started to double every three months and I began combination therapy. Since then my CD4 count has dropped below 500 only once, when I became resistant to one of the drugs. Since changing the combination, my viral load has been undetectable. Living with HIV in the era of combination therapy It is sometimes assumed that combination therapy has transformed the lives of people with HIV. Well, yes and no. In people who are HIV antibody positive it can postpone illness or an AIDS diagnosis. But in doing so it prolongs the uncertainty. The long-term efficacy of antiretroviral therapy is unknown. This brings dilemmas of its own. For example, many healthy people in mid-life seeing an advertisement for a pension plan might wish they could put more money aside for their old age. But an HIV antibody positive person has to ask him/herself



Being HIV antibody positive

“do I spend money and enjoy life now because there may not be an old age to save for, and risk impoverishment if there is; or do I save for old age and risk lying on a hospital bed in a year or two’s time regretting not spending my money and living life to the full while I was well?”. I can only imagine how much more acute and agonising dilemmas of this kind – involving trade-offs between present and future – must be in families where a parent and possibly also a child has HIV. There are other trade-offs, some more difficult than others. Never, for example, during all the years before combination therapy did I have to adapt my life to a medication regimen. It took some time to learn full adherence to the regimen, initially, I would simply forget very occasionally to take a dose when due. But, more fundamentally, adherence involves restricting freedoms that most of us take for granted – to eat what you want when you want, for example. It was difficult to adjust to my freedom being compromised by the treatment rather than the disease itself, although viewed in the light of the benefits of the treatment, these compromises were insignificant. Although public education has removed much of the fear and prejudice surrounding HIV and AIDS, there are communities where HIV remains highly stigmatised and where people with HIV are discriminated against. Discrimination, real or perceived, restricts the choices one is able to make in life; it limits life’s potential – a cruel irony when medicine has found ways to prolong life with HIV. Nor does combination therapy remove anxieties about falling in love and sexual intimacy. There is still the fear of revealing one’s status to a potential partner in case of rejection. Although my viral load is currently undetectable, I can’t assume that I’m not infectious. I must still insist on safer sex. The social acceptance of safer sex as normal, or at least sensible, behaviour means that asking for it is less likely to be met with rejection, but having sex with someone entails a risk, however small, that unsafe sex could occur. I know from experience that it isn’t always possible to be totally in control of an activity in which someone else is playing an equal part. However much I rationalise that preventing transmission is a shared responsibility, because everyone has a responsibility to protect themselves, and that anyone wanting unsafe sex is probably HIV antibody positive themselves, I know I would feel a tremendous sense of guilt and failure of moral responsibility if unsafe sex did occur. The HIV “veteran” I was aware before combination therapy arrived that I had remained well for an unusually long time since diagnosis. Now it seems that combination therapy may keep me alive and possibly well for many years more. During the millennium celebrations it occurred to me that, if adulthood begins at 18 years, I have lived with HIV for over half my adult life. I read recently that there is sometimes a striking similarity in how long-term survivors of HIV and war veterans describe their feelings about life. Both have had to confront their own mortality in a way that has led them to question, and sometimes reject, many of the assumptions which most people rely on to get through life. Large numbers of their peers and people they loved have died. As time goes on there there are fewer and fewer people with whom they have a shared life experience. War might have made life more intense for a while, but with the perspective of long hindsight there is some bitterness about the damage it has done to their lives. They have a strange sense of not knowing quite where they belong. This describes me pretty well.



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18



Having AIDS



Caroline Guinness



I was diagnosed in 1986 when there was very little knowledge of HIV. I had just been diagnosed as having precancer of the cervix, but I felt there was something else wrong – just an instinctive feeling – there was nothing in particular. So I went to my GP, and in fact saw a locum who was very young and enthusiastic. He felt my neck and said my glands were up, which I suppose alerted him to HIV, although he didn’t say anything, suggesting it might be glandular fever. He took some blood, and said I should return three days later. When I went back for the results he said they were negative for glandular fever, but that he had also requested an “AIDS test”. I remember feeling really cold when he said that. I knew that maybe that was what it was, because two years beforehand, shortly after my husband left me and I was very vulnerable, I had slept with a bisexual man. I told the doctor that I thought he should have talked to me about it first, and that I wanted the test stopped. He said it was too late as it had already gone to the laboratories. I said in that case I didn’t want to know what the result was. About two weeks later, my own doctor who was back, just turned up at my house. He knew that I didn’t want to know the result of the test, but he thought that, as an intelligent woman, I should know that it was positive. Even though I had some suspicions, I found that being told for definite was a different thing altogether. I went into shock. My first reaction was to ask how long I had to live, and he said probably about five years. My next thought was for my daughter, who was three years old at the time, and whether she would be infected too. The doctor didn’t think there would be any risk to her as I had obviously contracted it after she was born, but I knew nothing about transmission or anything like that. He suggested another doctor at the practice who had more experience than him, and had been treating a couple of gay men, and that I should go and see her, which I did. She was really sweet, but she didn’t know anything about other genitourinary medicine (GUM) clinics, voluntary agencies etc. On the other hand, she was good because she was a very firm believer in complementary therapies, so recommended vitamins and minerals and things which, looking back on it, was actually the best thing she could have done. But not having any counselling and not being in a specialist situation were not good. For the next six months or so I was just in denial – it hadn’t sunk in at all. I didn’t want to tell anybody because the atmosphere was really bad those days, lots of scaremongering in the Press, calling it the “gay plague” etc. I did tell a couple of close friends whom I lived with at the time. One, as a gay man, found it very ironic as he thought that if anyone should have tested positive it should have been him, and the other was a girlfriend of mine who sort of panicked. She was OK, but having lost her partner a couple of years before, she couldn’t bear the thought of losing somebody else, which of course didn’t help me. I didn’t want anyone like Social Services to know, as Lee had just started nursery school, and I didn’t want it getting out. So I just kept quiet and I continued in my state of denial. I couldn’t cope with work at all – it seemed irrelevant. I told my colleagues that I needed treatment for my cervix which I thought might help explain my lack of concentration. Their reaction was that it wasn’t such a big deal, and as I felt I couldn’t tell them what was really happening, I resigned. That 108



left me with financial problems, but I didn’t want to go to Social Services because of Lee. I had a partner at the time whom I had been with for six months before being diagnosed, and having to tell him, and him having to get tested was the other thing that was really frightening. Because I didn’t know how to tell him, I asked my best friend, whom he got on very well with, if he would tell him. My partner thought that he was going to be told I wanted to split up, so when he realised what it actually was, his initial reaction was one of relief, but the following two weeks, while he got tested and waited for the results, were pretty fraught. We had no information about transmission, but luckily the test came back negative, which was a relief. My fears about Lee being infected went on for quite some time because I felt I was not getting any real reassurance. I worried about things like her using my toothbrush, and I remembered I had cut my finger and she had helped me put the plaster on, and stuff like that. All those things kept going through my mind. The doctor I was seeing didn’t recommend that I had her tested, as she firmly believed Lee would be alright. Looking back on it, I think that if I had just had her tested then I would have felt a lot more reassured, because the whole issue bugged me subconsciously for a long time. Another very stressful event which happened that year was that a close friend of mine told me he had AIDS. He didn’t want anybody to know, and he asked if myself and a couple of other friends could look after him. His health went downhill so quickly and he started getting dementia and incontinence etc, and for me it was like looking in a mirror – very frightening. He did actually go public in the end, but he died shortly before Christmas, so all in all it was quite a bad year. In 1987, about a year after my diagnosis, through the Terrence Higgins Trust (THT) I finally found out about GUM clinics and I attended James Pringle House, Middlesex Hospital, which made a huge difference to me. I really wanted to meet other HIV positive women – I’d never met any, and still felt as if I was the only woman who had the virus. Someone at THT told me about a support group called Positively Women, who met once a week, so I went along to the group and met a couple of other positive women which helped a lot. I eventually became the Director of Positively Women, and the next three years were really hard work. There was nothing for women at all, so we tried to produce leaflets and information. Despite doing interviews and media work, I never went public about my HIV status. Although our slogan said “For positive women, run by positive women”, people never seemed to twig with me; I think they had some vision of what someone with HIV should look like, which I didn’t really fit into. Positive women were very much seen as drug users or prostitutes, and most of the women were keeping quiet, usually to protect their families. Through Positively Women, I did many hospital visits to AIDS wards and I used to find that stressful, worrying that I might catch something if I was going to see someone with meningitis or TB. However, after three years my energy was beginning to dwindle, and I also felt I wasn’t spending enough time with Lee, so in 1991, I resigned as the Director, and went part-time. It gave me a bit more time to myself, and because I felt so run down I started using complementary therapies such as acupuncture reflexology, which I’m still having, and which made a difference.



Having AIDS

I continued to attend the clinic every three months for a regular follow-up, and the relationship I had with my doctor was very good. She trusted my own judgement on my health, and I found we could work together. She also understood my need for complementary therapies. Seeing the same people on each visit helped maintain continuity and build up a relationship, which was important. I decided to tell my daughter when she was about 10 years old. She’s very bright and reads the newspapers, and it seemed the right time for her. Although I had never gone public about it, I knew it was going to get out at some point, and I didn’t want Lee to find out from anyone else. I thought Lee might suspect, but in fact she hadn’t. Her first reaction when I told her was to burst into tears, and then she felt embarrassed about crying which made me feel awful as it was quite a natural reaction. For a week or so she kept asking me how I was, and if there was anything in particular that she could do to help. I said she could give me a hand with the housework, but that didn’t last very long – I don’t think that was what she was expecting! It became immediately apparent that there were no services for children, and she was desperate to meet other kids in the same situation. I suggested to Lee that she didn’t tell any friends for a while until she got used to the fact. Anyway she did actually tell a schoolfriend who immediately told everyone else which was exactly what I didn’t want to happen. Her school had been helpful – I had spoken to the Head, her teacher, and the school counsellor before telling her, but she still needed to talk to a trained counsellor, and again she needed to meet other kids in the same situation. None of the organisations offered services for children, but I got a letter from a woman in a similar situation and we met up so that Lee could meet her daughter, which was good for both of them, and at least she knew she wasn’t on her own. Lee also started seeing a child psychologist which she really benefited from and she still goes along there when she wants to, but nothing regular. I think that over the last year or so my energy really hasn’t been so good, and as Lee has now reached 13 and is going through everything that 13 year olds do, I could really do with some help now. Her father was in Australia when I was diagnosed, and I didn’t want to tell him by ’phone or letter, so I was hoping that he would be coming over to the UK at some point. Because I’d been told that I had about five years to live, I wanted to sort things out as quickly as possible. Anyway, he did come over and I told him, and he had a really odd reaction: he seemed to think I was trying to emotionally blackmail him, which really upset me. It was only later that I found out through a mutual friend that he felt that if he hadn’t left me for someone else, I would never have slept with this bisexual man, and so he felt responsible, a thought which had never entered my head. His whole reaction was one of pure guilt, but then over the years that all changed, and for the last few years he’s been really supportive. At the beginning of 1992 I found I was pregnant, and I decided I wanted a termination, and that at the same time I wanted to be sterilised as I didn’t want to go through this worry again. I knew enough about transmission at that point to know there was a 10–15% chance that I could pass the virus on, and although that’s quite a low risk, I had seen enough other women take the chance and go through the whole nine months and following 18 months not knowing whether the child was infected or not, and I felt I didn’t have that in me. I was referred to a hospital and I went there and saw a doctor in outpatients. She knew nothing about HIV – absolutely nothing. She automatically assumed I would want a termination, and before she examined me she removed all the blankets and coverings from the table, so again obviously had no idea about transmission or anything. She also asked the nurse what precautions she should be taking in front of me. It made me feel awful at what was a traumatic time anyway. About a month ago I was involved in a conference called Living Proof, the first conference for long-term survivors ever, which was really illuminating and quite empowering. There were a lot of other women there which was great to see. I went to three workshops during the two-day event and it was amazing how the experiences of both women and men were so similar. We had all been told first that we probably had five years, then seven years, then 10 years etc. Although my Consultant never said this, it had been the general consensus, and the type of the thing you read in the press, so that when you go past those dates you feel more and more isolated. When you have also suffered so much loss and lost so many people on the way, there is a tinge of guilt that you are still here. Friends whom I told originally have sort of forgotten about it now because it’s been going on for so long and they don’t seem to realise that I’m still going through it all, and that it takes a large chunk out of my life, that I had to resign my job and go onto benefits. You feel that people are waiting for you to die. It’s still the uncertainty of just not knowing, constantly trying not to be in denial, because there’ve been enough people I know who have had the virus longer than I have and have died, and I do have definite symptoms. If I was in America I would have been diagnosed as having AIDS a while ago because my CD4 count has been hopping between 150 and 200 over the last two years. Luckily they don’t do that here, because psychologically that’s a hard one. When I was admitted into hospital last year, the doctor was trying to be reassuring, saying that it wasn’t necessarily HIVrelated, but I didn’t believe it. I found that most of the nurses had had no specialist training which made me feel a bit vulnerable. One morning I woke to find a young agency training nurse looking at my file; she said, “Oh, you were diagnosed in 1986 and you’re still alive – that’s amazing”, and I thought “I just don’t need this, I really don’t”. I was feeling so ill and didn’t really have the strength to deal with it. When you live in a little closed society like I do medically, where you go into a clinic, where everybody is wonderful and the service is fantastic, you forget about the lack of knowledge and the attitudes outside that world.



Update since 4th edition

It is now the year 2000 and I am still here. I am amazed at just how much my life has changed over the last four years, not to mention the changes in medical advances, from which I have benefitted greatly. In 1996 I became steadily more and more ill. I was suffering from constant night sweats, my face was covered in molescums, warts appearing everywhere, my hair falling out in huge clumps, my weight plummeting and the most appalling constant fatigue, it was as much as I could do to get a meal together for Lee on her return from school. This was very frightening for her. Finally I came down with pneumonia and having just recovered from that, I immediately got E. coli septecaemia and very nearly died. While I was in hospital it was suggested that I start on combination therapy – I felt I had nothing to lose and agreed. The viral load test had just come in and my count was nearly one million, and my T cells were hovering around 50. To my mind I had no choice but to begin treatment. I started with “Dual Combination” (which is not advisable today). I was taking 3TC and D4T. Almost immediately I started to feel better. My viral load became undetectable, my T cells rose to over 200, my hair stopped falling out, the 109



ABC of AIDS

molescums disappeared, as did the warts, the night sweats stopped, but the most remarkable thing for me was to suddenly be flooded with masses of energy. I experienced complete euphoria. The psychological effects were strange. Having prepared myself for death I found myself strangely afraid of life. I had been forced to opt out of the “rat race”, which in a way was rather comforting. Now I needed to join it again. I realised that I had missed years of planning for a future. No pension plans, no savings etc . . . I also felt a strong sense of “survivor’s guilt”. I had lost so many close friends and colleagues, and asked myself the question “why me”? Out of the 600 or so women who used Positively Women there were only four of us left from the original group. I decided to start from the beginning again and threw myself into working in the music and film business. After 18 months I developed a strange side-effect – lipodystrophy. My fat just disappeared off my arms and legs, I had no buttocks to speak of and my face aged about 20 years. My breasts grew enormous and I had a bulging stomach. My viral load was at this point about 5000 and my T cells were dropping again. I decided to see if my body would return to its normal shape and to discontinue any form of treatment. I was still on 3TC and D4T. After about four months, all my old HIV symptoms were reappearing. My viral load reached 650 000 and my T cells were around 50. The lipodystophy had not changed at all – if anything it was worse – but this could have been “AIDS wasting”. Time for a new combination. At this point (September 1998), dual combination was not recommended and I started on triple combination – DMP, AZT and DDI. It took longer for this to work than the last combination, but after about three months my viral load was below 50 and my T cells ranged between 200 and 250. I am still on this combination and still undetectable and, much to my doctor’s surprise, my body fat has gone back to normal. My triglycerides are still high, but I have the weight back on my buttocks, arms, legs and face – and it seems to get better by the day. I have recently married a wonderful man, Lee is now 17 and life goes on. I am more confident of a future, but by no means complacent. I see too many of my peers suffering appalling side effects or complete treatment failure for me to take my life for granted. If I am still around for the next edition of the ABC of AIDS, I am sure it will all have changed just as radically again – watch this space.



110



Index



abacavir 72 ablation 28 abscesses 77 accuracy, testing 8, 9 aciclovir 20, 40, 50 addictive drug users see injection drug use adenoviruses 39 adrianycin 27 advice, to patients 22 Africa epidemiology 3 prevention strategies 103 AIDS case definitions 1–2, 62 personal account 108–10 albendazole 39 allopurinol 27 alpha interferon 44 amikacin 53 amphetamines 72 amphotericin B 36, 52 anaemia 20–1 anal disease herpes simplex 40 tumours 29 anal sex, unprotected 101 analgesics 20, 90 anorexia 39 antenatal testing 74–5 anthracyclines 26 antiangiogenics 26 antibiotics 20 antibodies beneficial effects 14 development of 13 harmful effects 14 positivity to see seroconversion tests accuracy 8 pre-test discussions 82–3 pregnant women 104 understanding of prevalence 4 anticonvulsants 52, 90 antidepressants, tricyclic 90 antidiarrhoeal agents 49 antiemetics 49, 91, 92 antifungals 19, 20 antigens tests for 8, 9–10 see also specific antigens antiretrovirals children 78–9 clinical effectiveness 53–4 counselling 85 developing countries 63–4 drug interactions 35, 72 drug users 71–2 malignancies 28 mitochondrial dysfunction 75



MTCT 75 new agents 58 plasma viral load 55–6 primary infection 56–7 resistance 10, 57 survival 21 toxicities 57–8 types 46 anus see anal disease anxiety see fear appetite stimulants 39 ART see antiretrovirals arterial blood gases 31 Aspergillus fumigatus 36 asymptomatic infection 18 atovaquone 32, 33, 47, 48 azithromycin 48, 53 AZT see zidovudine B lymphocytes 13, 26 bacterial infections children 77 developing countries 60 diarrhoea 38 IDU 69 lung 31, 34 treatment 52–3 see also specific bacteria/diseases Barré-Sinoussi 7 basic fibroblast growth factor 24, 26 behaviours, risk of infection 100, 101 benzodiazepines 68, 69, 71, 90 biopsies lymph nodes 13, 18 open lung 31–2 transbronchial 34, 37, 46 bisexual men 101–2 bleomycin 25, 27, 28, 34 blood, for testing 11 blood donors testing of 10 transmission to and from 59 blood gases, arterial 31 blood products 2, 105 blood transfusion 2, 105 bone marrow 26, 27, 28 “boredom”, risk behaviour 101 brain see central nervous system breastfeeding, MTCT 74 breath, shortness of 69 bronchoscopy fibroeptic 31, 34 precautions 95 Campylobacter 38, 53 cancer see tumours Candida albicans 52 candidiasis oesophageal 20



111



Index oral 19, 20, 38, 52, 77 vulvovaginal 52 cannabis 69 carbamazepine 90 carriers in community 97 hospital care 96 WHO estimates 6 case definitions 1–2, 62 CCR5 12 CD4 T cells activation of 16 counts AIDS definition 1 anal cancer 29 asymptomatic infection 18 children 76, 81 classification of HIV 17 cryptosporidiosis 39, 48, 49 cytomegalovirus 37, 50 dementia 45 diarrhoea 38 monitoring infection 14–15 neurological manifestations 42 non-Hodgkin’s lymphoma 26 P. carinii 33, 47 primary cerebral lymphoma 27 primary infection 56 prognostic indication 21 toxoplasmosis 43, 48 tuberculosis 35 fall in, after infection 13 HIV replication in 6 HIV target 12 treatment with cytokines 58 CD8 T cells beneficial effects 14, 15 responses to CMV 51 responses to HIV 56 rise in, after infection 13 cellulitis 78 Centers for Disease Control (CDC) AIDS-defining malignancies 23 case definition of AIDS 1–2, 62 classification of HIV 17, 76 Central Africa 3 central nervous system lymphoma 27–8, 44–5 toxoplasmosis 43, 48, 61 see also neurological manifestations cerebral disease see central nervous system cervical cancer 21, 28 chemokines 12, 14 chemoprophylaxis 36 chemotherapy cervical cancer 28 Hodgkin’s lymphoma 28–9 KS 25, 34 non-Hodgkin’s lymphoma 27 chest radiology 30 fungal pneumonia 36 KS 24, 34 lobar pneumonia 34 lymphocyte interstitial pneumonitis 37 P. carinii 31, 32, 33, 46 pleurally based lymphoma 36 112 tuberculosis 35, 60 children antenatal testing 74–5 clinical manifestations 76–8 diagnosis 76–7 epidemiology 2, 3, 75–6 management 78–81 mother-to-child transmission 74–5 natural history 76–8 prognostic markers 78 seropositivity, KS 24 see also infants chimpanzees 6 Chlamydia trachomatis 40 chlordiazepoxide 67 chlorhexidine 20 choice, facilitating 93 cholangitis, sclerosing 40 cholestasis 40 CHOP chemotherapy 27 cidofovir 44, 50–1 ciprofloxacillin 53 clarithromycin 48, 53 classification of HIV 17–18 HIV infection in children 76 lymphoma 26 of pain 89 clindamycin 32, 46, 47, 48 clinical aspects 12 children 76–8 developing countries 60–2 clinical waste 97 clofazimine 53 clonazepam 90 clonidine 90 Clostridium difficile 39 clotrimazole 20 clotted blood, for testing 11 CMV see cytomegalovirus co-codamol 89 co-dydramol 89 co-receptors 12 co-trimoxazole 21, 32, 33, 43, 46, 47, 48, 53, 63, 81 cocaine 72 colitis 39 colposcopy 28 combination therapy 106–7 counselling 85 directly observed 71 community agencies 85 community aspects 97 complementary therapies 81 compound pains 91–3 computed tomography 43, 44–5, 48 condoms 101 confidentiality 21–2, 84 confirmatory tests 8–9 confrontation, drug user patients 67 consent 87 constitutional symptoms 19 contact, with drug users 66, 67 control policies 95–8 controlled drugs, prescriptions 68 coping strategies 83, 84, 85 core protein see p24



Index corticosteroids 47, 48 costs, of AIDS 5 cough 69 counselling being HIV positive 106 defined 82 inoculation injuries 98 linking agencies 85 need for 82–3 psychological issues 83 responses to results 84 skills 83 therapy 85 voluntary 104–5 worried well 85 cryptococcal meningitis 42, 43, 52, 61 Cryptococcus neoformans 36, 42, 43 cryptosporidiosis 48–9, 77 Cryptosporidium spp. 39 CSF abnormalities 42, 43 cutaneous disorders see skin disorders CXCR4 12 cyclophosphamide 27 Cyclospora sp. 39 cytokines growth of KS cells 24 treatment with 58 cytomegalovirus brain 44 children 77 colitis 39 lungs 37 treatment 50, 51 cytosine arabinoside 44 cytoxic cells see CD8 cells dacarbazine 28 dapsone 32, 35, 47, 48, 52 daunorubicin 25, 34 death children 77, 78 drug users 72 managing 86–7 pre-AIDS, drug users 69 decision-making, with patients 87 decontamination 97 definitions, AIDS 1–2, 62 delavirdine 35, 72 dementia 45, 69, 70 dendritic cells 12–13 dentists, transmission by 96 deoxyguanosine 50 dependency, IDU-related HIV 66 dermatitis pruriginous 59, 60 seborrhoeic 19, 20 developing countries 59–64 ART 76 case definitions of AIDS 62 clinical aspects 60–2 control of STIs 105 epidemiology 3, 59 natural history 59–60 public health authorities 64 staging of HIV 62, 63 developmental needs, children 81 dexamethasone 27 diamorphine 71 diarrhoea 38–9 cryptosporidiosis 49 developing countries 61 IDU 69 diazepam 68, 90 diclazuril 49 didanosine 72 directly observed therapy 35, 72 discriminating tests 8 disinfection 97 DNA, tests for 9–10, 76 doxorubicin 25, 27, 28, 34 drug abusers see injection drug use DSPN 45 dying patients 92–4 education, health 99–100 efavirenz 57, 72 ELISA 77 emotional support 22 encephalitis 44, 70 Encephalitozoon intestinalis 39 encephalopathies children 78 drug users 70 see also central nervous system Entamoeba hystolytica 39 enteral nutrition 39 Enterocytozoon bienusi 39 epidemiology 1–5 children 74–5 developing countries 59 epidurals 90 epilepsy 69 Epstein-Barr virus 20, 26, 27, 77 erythromycin 49 ethambutol 53 ethnic minorities, prevention strategies 103 Europe, epidemiology 4 evaluation, pain 88–89, 91 excision 28 exposure-prone procedures 96 eye, CMV infection 44, 50 false results, tests 8, 13 famciclovir 20, 50 families care of children 81 counselling for 84 dying patients 93 impact on 3 fatigue 69 fear of infection 85 of pain 67–8 fever 69 fire hazards, IDU 66, 67 first aid 98 first aid kits 105 flecainide 90 fluconazole 20, 36, 52 flucytosine 52 flumazenil 68–9 folinic acid 32, 47 113



Index folliculitis 20 follow-up tests 8–9 foscarnet 39, 40, 50, 51 fungal infections lungs 31, 36 skin 60 treatment 51, 52 see also specific fungi/diseases furosemide 92 gabapentin 90 Gallo 7 ganciclovir 39, 40, 50, 51 gastrointestinal manifestations 38–41 KS 25 gay community 100–1 genome sequences, tests for 9–10 genotypic mutations 54, 57 germ cell tumours, testicular 29 glandular fever, differential diagnosis 18 global epidemiology 2–5 glucocorticoids 33 glycopyrronium 92 gp41 15 gp120 12, 15 granulocyte colony-stimulating factor 24, 50 Guidelines on Clinical Management, Drug Misuse and Dependence 65, 68 GUM clinics 101, 104, 105 gut see gastrointestinal disorders Guthrie cards 73 HAART dementia 45 fungal infections 52 immunotherapy 16 infants 79 KS 25, 26 life expectancy 4 lung disease 32 MTCT 75 PML 44 risk behaviour 100 tumours 23, 29 viral infections 51 haematological problems 20–1 Haemophilus influenzae 34, 69, 77 hairy leukoplakia 19, 20 health care workers carriers 96 transmission of HIV 2 health education 99–100 helper T cells see CD4 T cells hepatitis B disinfection 97 drug use 65 drug users 69–70 hospital care 96 response to vaccination 40 hepatitis C drug use 65 drug users 40, 69–70 heroin 72 herpes simplex anogenital disease 20, 40 treatment 38, 50 herpes virus-8, human 23–4, 25, 29 114 herpes zoster see varicella zoster virus heterosexual transmission 4, 59, 99, 103 highly active antiretroviral therapy see HAART Histoplasma capsulatum 36 HIV AIDS-defining conditions 1 origin 6 related viruses 7 tests see tests vaccine development 15–16 HIV infection care and pain control 86–94 children 73–81 clinical aspects 12 control policies 95–8 counselling 82–5 developing countries 59–64 development of epidemic 2–5 gastrointestinal and hepatic manifestations 38–41 history and management of 17–22 immune responses 12–13, 14 injection drug use 65–72 lungs 30–7 monitoring 14–15 neurological manifestations 42–5 personal account 106–7 prevention strategies 99–106 transmission see transmission treatment see management tumours in 23–9 see also specific diseases and (types of) pathogens HIV-1 developing countries 59–60 origin 6 tests 8 transmission 7 HIV-2 developing countries 59–60 origin 6 prevalence 7 progression 60 tests 8 transmission 7 West African connection 1 Hodgkin’s disease 28–9 home testing 9, 10 homosexual transmission 59 horizontal transmission 7 hospital care drug users 67 infection control 95–6 HPV, cervical carcinoma 28 HTLV viruses 7 human herpes virus-8 23–4, 25, 29 human immunodeficiency virus see HIV human papilloma virus 28, 29, 40 hydrocortisone 19, 20 hyoscine 92 hypergammaglobulinaemia 77 hyperimmune bovine colostrum 49 hypertonic saline test 31 hypogammaglobulinaemia 75 hypoxaemia 47 IDU see injection drug use illegal drug use, on wards 67



Index imidazole 52 immunisation 15–16, 80 immunoglobulin infusions 80 response to HIV 8 (IgG) transfer to infants 75–6 immunopathology 12–13 immunotherapy 16 impetigo 20 indinavir 72, 98 infants CD4 counts 76 HAART 79 P. carinii 61 transfer of IgG 75–6 infection see HIV infection information, for patients 11, 22, 83 injection drug use 65–72 malignancies 28 management strategies 66–8 medical care systems 65–6 medical problems 69–72 prevention strategies 102–3 transmission by 59 inoculation injuries 96, 98 interferon 40, 44 interleukin 2 16, 58 interleukin 6 24, 26 intracranial hypertension 43 invasive tests, lung disease 31–2 isoniazid 35, 36, 52, 63 Isospora belli 39, 61 isosporiasis 49 Italy, malignancies 28 itraconazole 36, 52 izoniazid 80 jaundice 69 JC virus 43–4 Kaposi’s sarcoma 1, 23–6, 29, 63 children 78 developing countries 61 drug users 70 gastrointestinal tract 41 lung disease 30, 34–5 ketoconazole 20, 52 KS see Kaposi’s syndrome KSHV see human herpes virus-8 lamivudine 57, 75, 98 lesions KS 24, 25, 41 PCNSL 44 letrazuril 49 leucopenia 32 lidocaine 90 life expectancy 3, 4 liposomes 25 liquid disinfectants 97 lung disease 30–7 bacterial infections 34 cancer 29, 37 children 77 cytomegalovirus 37 fungal pneumonia 36 IDU 69 investigations 30–2 KS 34–5 lymphocyte interstitial pneumonia 37 lymphoma 36 non-specific pneumonia 37 opiates 68 Pneumocystis carinii pneumonia 32–4 tuberculosis 35–6 lung function tests 31 lung secretions 92 lymph nodes in KS 24 persistent generalised lymphadenopathy 13, 18 lymphadenopathy IDU 69 persistent generalised 13, 18 lymphangioma-like KS 24 lymphocyte interstitial pneumonia 37, 77 lymphocytes replication of virus 7 see also specific types lymphokines 12 lymphoma children 78 gastrointestinal tract 41 Hodgkin’s 28–9 lung disease 30, 36 non-Hodgkin’s 26–7 primary cerebral 27–8, 44–5 lymphopenia 14, 20 macrolides 48 macrophages 12–13, 26 magnetic resonance imaging 43, 44–5, 78 malaria 61 malignancies see tumours management/treatment bacterial infections 52–3 children 78–81 developing countries 63–4 early HIV infection 17–22 fungal infections 51, 52 IDU-related HIV 66–8 IDU-related problems 67–70 protozoal infections 46–9 types of 46 viral infections 49, 50–1 see also specific disorders and methods medazolam 71 medical care, drug users 65–6 megestrol acetate 39 memory 69 meningitis, cryptococcal 42, 43, 52, 61 methadone 68, 71, 72, 102 methotrexate 27 methylprednisolone 33 metronidazole 20 microsporidia 39, 49 monocytes 13 Montagnier 7 morphine 71, 89, 90 mortality see death; dying patients mother-to-child transmission 59, 64, 74–5 mouth problems 19, 20 movement-related pain 92 115



Index MTCT see mother-to-child transmission multi-drug resistant tuberculosis 36, 53 multidisciplinary teams, care of children 81 Mycobacterium spp. avium complex/avium intracellulare 52, 53, 60, 61 children 77, 80 diarrhoea 38 neurological manifestations 42 tuberculosis see tuberculosis naloxone 68 natural history 17–22 children 76–8 in developing world 59–60 nausea 91–2 needles exchange programmes 102 sterile packs 105 transmission by 2 Neisseria gonorrhoea 40 nelfinavir 72, 79 neonates seropositive 73–4 testing 74–5 neoplasms see tumours neurological manifestations 42–5 children 77 clinical approach 42 developing countries 61 opportunistic infections 43–4 neuropathic pain 90 neutropenia 20–1, 50 nevirapine 57, 72, 75 nociceptive pain 90 non-Hodgkin’s lymphoma 26–7, 29 non-invasive tests 8–9 lung disease 30–1 non-medical symptom control 88 non-nucleoside RT inhibitors 35, 52, 54, 55, 57, 72, 75 non-steroidal anti-inflammatory drugs 89, 92 nucleoside RT inhibitors 54, 55, 58, 72 nystatin 20 occult bacteraemia 77 octreotide 90 oesophageal disease 25, 38 Oncostatin M 24 open lung biopsy 31–2 opiates lung disease 69 nociceptive pain 89 pain management 71 side effects 68, 89 toxicity 89 withdrawal from 68 withdrawal symptoms 67 opportunistic infections children 77 drug users 70 neurological manifestations 43–4 prophylaxis 21 treatment 63 oral conditions 19, 20, 25, 38, 52, 77 orphans 3 osteomyelitis 77 oximetry 31 116



p24 in diagnostic tests 9, 76 disease progression 14 paclitaxel 26 paediatric AIDS see children pain classification 88 compound 90–2 fear of, drug users 67–8 management 88–90 children 81 IDU-related HIV 71 in the last few days 93 movement-related 92 neuropathic 90 therapeutic approach to 90 palliative care 86–94 paracetamol 89 partners, counselling for 84 patients consent 87 counselling 82–5 decision-making 87 discussing prognosis 87 general management 21–2 partnership with 87 testing of 10–11 see also dying patients peer support 106 penicilliosis 61 Penicillium marneffei 61 pentamidine 32, 33, 46, 47 peripheral nerve disorders 45 persistent generalised lymphadenopathy 13, 18 personal accounts having AIDS 108–9 HIV antibody positive 106–7 phenotypic resistance 57 phenytoin 72, 90 PHI see primary HIV infection plasma viral load ART 55–6 non-breast-fed infants 78 platelet-derived growth factor 24 pleural effusions 35 pneumococcal infections 60, 63, 77 pneumococcal polysaccharide vaccine 80 Pneumocystis carinii 1 African infants 61 bacterial cause 31 chest radiograph 31 grading of severity 32 IDU-related HIV 69 pneumonitis 37 prophylaxis 27, 30, 33–4, 35 treatment 32–3, 46–8 pneumonia see lung disease pneumonitis 37 policies, control of infection 95–8 poliomyelitis 80 polymerase chain reaction, in tests 9, 10, 11, 43–4, 76 polyradiculopathy, CMV 44 Popovic 7 post-test counselling 83–4 pre-AIDS deaths 69



Index pre-terminal restlessness 93 pre-test discussions 82–3 prednisolone 27, 33 pregnancy antibody testing 104 terminations 82 prescribing controlled drugs 68 IDU 66–7 pain management 89–90 prevention/risk reduction children 80, 81 counselling 83 strategies 99–106 primaquine 32, 46, 47 primary CNS lymphoma 27–8, 44–5 primary HIV infection 17–18 treatment 56–7 prognosis, discussing 87 prognostic markers 21, 78 progression HIV-2 60 IDU-related HIV 71 risk of 21 progressive multifocal leucoencephalopathy 43–4 protease inhibitors 35, 52, 54, 55, 58, 72, 79 protozoal infections 46–9 diarrhoea 39 pruriginous dermatitis 59, 60 Pseudomonas aeruginosa 34 psychological responses, positive results 84 psychological support 22 psychosocial management, patients 82–5 public health programmes 64 pulmonary disease/function see lung pyrazinamide 52 pyrimethamine 33, 48 quantity/quality equation 86–7 radiotherapy cervical cancer 28 KS 25 lymphoma 27 re-socialisation, IDU 67 recombinant human growth factor 39 recreational drug use anti-viral therapy 71 medical care 65, 66 medical effects 68 referrals 106 regional variation, developing countries 61 religious beliefs 94 rescue services 97 resistance, to drugs 10, 57 respiratory disease see lung retinitis, CMV 44, 50 retirement 106 retroviruses 6, 7 reverse transcriptase 6 reverse transcriptase inhibitors 54 rifabutin 35, 52, 53 rifampicin 35, 36, 52, 53, 72, 80 risk behaviour 103 ritonavir 35, 72 RNA, tests for 9–10, 76 safe sex 7, 83, 85, 99 saline induced sputum 31, 46 saliva, in testing 9 Salmonella spp. 38, 53, 60, 77 sarcoma see Kaposi’s sarcoma Schistosoma mansoni 61 screening kits 8 screening tests see tests seborrhoeic dermatitis 19, 20 sedative drugs, IDU 68 seizures 69, 78 self-test kits 10 septic arthritis 77 septicaemia, bacterial 60, 69 seroconversion 17–18 development of 17 KS 24 neurological symptoms 42 seropositive persons counselling 83–4 potentially infectious 7 prevention interventions 103–4 psychological responses 84 sexual transmission 2 control and testing 105 counselling 104 preventing 100–1 young persons 99 sharps disposal 96–7 Shigella 38 shingles see varicella zoster virus SIV 7, 15 skin disorders 19–20, 60 KS 24, 25 skin punctures 98 “slim” disease 59, 61 smoking policies, IDU 67 social effects, HIV infection 65, 66 sodium valproate 72 sooty mangabey monkeys 6 South Africa, epidemiology 3 Spain, malignancies 28 specimen samples disposal 96 taking and transporting 11 spindle cells 24 spiramycin 49 splashes 98 sputum induction 31, 46 staging system, HIV 62, 63 Staphylococcus spp. 34, 77 statutory agencies 85 stavudine 72 sterile kits 105, 106 Streptococcus spp. 34, 69, 77 sub-Saharan Africa 3 suffering 90–1 sulphadiazine 48 sulphamethoxazole 39 supportive care 67, 81 surrogate markers 21, 78 surveillance, case definitions for 62 survival antiretrovirals 21 IDU-related HIV 71, 72 symptom control 87–92 117